Substituted aminothiazoles as inhibitors of cancers, including hepatocellular carcinoma, and as inhibitors of hepatitis virus replication

ABSTRACT

Pharmaceutical compositions of the invention are presented which comprise substituted aminothiazoles derivatives. The substituted aminothiazoles derivatives have a disease-modifying action in the treatment of diseases associated with unregulated cell growth. Such diseases include cancers such as hepatocellular carcinoma, and viral infections from a hepatitis virus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/542,907 filed Oct. 4, 2011, which is herein incorporated by referencein its entirety.

FIELD OF INVENTION

The present invention describes compounds and methods useful for thetreatment of cancer, including primary liver cancer, hepatocellularcarcinoma, hepatoblastoma, and cholangiocarcinoma, and the treatment ofviral hepatitis infection, including but not limited to hepatitis Avirus infection, hepatitis B virus infection, hepatitis c virusinfection, hepatitis D virus infection, and hepatitis E virus infection,as well as other viral species that infect the liver.

BACKGROUND OF THE INVENTION

Primary liver cancer is currently the fifth most common cause of cancerdeaths among men, and ninth among women in the US, with the numbersincreasing yearly. The most recent data indicate that in 2008 there werean estimated 21,370 new cases of liver and bile duct cancer of which themajority are hepatocellular carcinomas (HCCs), with 18,410 deaths(Institute, N.C., SEER Cancer Statistics Review, 1975-2005, Ries LAG, etal., Editors, 2008.). Worldwide, it is the fourth most common cancer,with approximately 663,000 fatal cases reported in 2008; based oncurrent trends and baseline models, the incidence is expected to rise to756,000 in 2015, and 955,000 in 2030 (Mathers, C. D. and D. Loncar,Projections of global mortality and burden of disease from 2002 to 2030.PLoS Med, 2006. 3, 11, p. e442.). Although it is comparatively uncommonin the US, its incidence has been rising over the last 20 yearspartially as a result of burgeoning numbers of cases of chronichepatitis C (Caldwell, S. and S. H. Park, the epidemiology ofhepatocellular cancer: from the perspectives of public health problem totumor biology. J. Gastroenterol, 2009, 44 Suppl. 19: p. 96-101.El-Serag, H. B., et al., the continuing increase in the incidence ofhepatocellular carcinoma in the United States: an update. Ann InternMed., 2003. 139(10): p. 817-23) one of the principal causes along withhepatitis B and aflatoxin exposure.

There is a long felt need for new drugs that are both disease-modifyingand effective in treating patients with primary liver cancer, includingbut not limited to hepatocellular carcinoma, hepatoblastoma, andcholangiocarcinoma. There is also a clear and present need for newtherapeutic agents that are both disease modifying and effective intreating patients that are infected with a hepatitis virus. The presentinvention addresses the need for new drugs that are bothdisease-modifying and effective in treating patients suffering fromprimary liver cancer and hepatocellular carcinoma. Because the presentinvention targets the cell types that have been demonstrated to supportviral infection in the liver, the present invention addresses also theneed for new antiviral drugs that are both disease-modifying andeffective in treating patients that are infected with hepatitis A virus,hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis Evirus, as well as other viral species that infect the liver.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed toward novel substitutedaminothiazoles, compounds of formula (I),

Including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein:R¹ is selected from a group consisting of hydrogen, C₁-C₉ linear alkyl,isopropyl, cyclohexyl, bromine, cyano,

R² is selected from a group consisting of hydrogen, methyl, isopropyl,tert-butyl, benzyl, and

Ar¹ is selected from a group consisting of phenyl,

Ar² is selected from a group consisting of phenyl,

Compounds of the structures

are excluded from the novel compounds of formula (I).

The present invention is also directed toward novel methods of use ofcompounds of the structures.

The present invention further relates to compositions comprising:

an effective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing diseases that involve unregulated cell growth, including, forexample, primary liver cancer, hepatocellular carcinoma, hepatoblastoma,cholangiocarcinoma breast cancer, ovarian cancer, lung cancer, leukemia,and metastatic disease, said method comprising administering to asubject an effective amount of a compound or composition according tothe present invention.

The present invention yet further relates to a method for treating orpreventing diseases that involve unregulated cell growth, including, forexample, primary liver cancer, hepatocellular carcinoma, hepatoblastoma,and cholangiocarcinoma, breast cancer, ovarian cancer, lung cancer,leukemia, and metastatic disease, wherein said method comprisesadministering to a subject a composition comprising an effective amountof one or more compounds according to the present invention and anexcipient.

The present invention also relates to a method for treating orpreventing disease or conditions associated with primary liver cancer,hepatocellular carcinoma, hepatoblastoma, and cholangiocarcinoma, breastcancer, ovarian cancer, lung cancer, leukemia, and metastatic disease,and diseases that involve unregulated cell growth. Said methods compriseadministering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with primary liver cancer,hepatocellular carcinoma, hepatoblastoma, and cholangiocarcinoma, breastcancer, ovarian cancer, lung cancer, leukemia, and metastatic disease,and diseases that involve unregulated cell growth, wherein said methodcomprises administering to a subject a composition comprising aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing disease or conditions associated with unregulated cellgrowth. Said methods comprise administering to a subject an effectiveamount of a compound or composition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with unregulated cellgrowth, wherein said method comprises administering to a subject acomposition comprising an effective amount of one or more compoundsaccording to the present invention and an excipient.

The present invention also relates to a method for treating orpreventing diseases that involve infection with a hepatits virus,including, for example, hepatitis A virus, hepatitis B virus, hepatitisC virus, hepatitis D virus, and hepatitis E virus, as well as otherviral species that infect the liver, said method comprisingadministering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing diseases that involve infection with a hepatitis virus,including, for example, hepatitis A virus, hepatitis B virus, hepatitisC virus, hepatitis D virus, and hepatitis E virus, as well as otherviral species that infect the liver, wherein said method comprisesadministering to a subject a composition comprising an effective amountof one or more compounds according to the present invention and anexcipient.

The present invention also relates to a method for treating orpreventing disease or conditions associated with hepatits A virus,hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis Evirus, and diseases that involve infection with a hepatitis virus aswell as other viral species that infect the liver. Said methods compriseadministering to a subject an effective amount of a compound orcomposition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with hepatitis A virus,hepatitis B virus, hepatitis C virus, hepatitis D virus, and Hepatitis Evirus, and diseases that involve infection with a hepatits virus as wellas other viral species that infect the liver, wherein said methodcomprises administering to a subject a composition comprising aneffective amount of one or more compounds according to the presentinvention and an excipient.

The present invention also relates to a method for treating orpreventing disease or conditions associated with infection with ahepatits virus, as well as other viral species that infect the liver.Said methods comprise administering to a subject an effective amount ofa compound or composition according to the present invention.

The present invention yet further relates to a method for treating orpreventing disease or conditions associated with infection with ahepatits virus, as well as other viral species that infect the liver,wherein said method comprises administering to a subject a compositioncomprising an effective amount of one or more compounds according to thepresent invention and an excipient.

The present invention further relates to a process for preparing thecompounds of the present invention.

These and other objects, features, and advantages will become apparentto those of ordinary skill in the art from a reading of the followingdetailed description and the appended claims. All percentages, ratiosand proportions herein are by weight, unless otherwise specified. Alltemperatures are in degrees Celsius (° C.) unless otherwise specified.All documents cited are in relevant part, incorporated herein byreference; the citation of any document is not to be construed as adadmission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The substituted aminothiazoles of the present invention are capable oftreating and preventing diseases associated with unregulated cellgrowth, for example primary liver cancer hepatocellular carcinoma,hepatoblastoma, and cholangiocarcinoma, breast cancer, ovarian cancer,lung cancer, leukemia, and metastatic disease. The substitutedaminothiazoles of the present invention are also capable of treating andpreventing diseases associated with infection with a hepatits virus, forexample hepatitis A virus, hepatitis B virus, hepatitis C virus,hepatitis D virus, and hepatitis E virus, as well as other viruses thatinfect the liver. It has been discovered that compounds of thedisclosure cause cell cycle arrest and apoptosis in hepatocellularcarcinoma (HCC)-derived cells as well as hepatoblastoma, breast cancercells, and ovarian carcinoma cells. In addition, it has been determinedthat the effect on sensitive cells, for example HCC-derived cells aswell as hepatoblastoma, breast cancer cells, and ovarian carcinomacells, is non-reversible, and that the compounds of the disclosure actthrough inhibition of mitotic anti-apoptotic signaling by the regulatorykinases AKT, mTORC1 and mTORC2. Further, the substituted aminothiazolesof the disclosure destroy cells that support infection with a hepatitsvirus, for example hepatitis A virus, hepatitis B virus, hepatitis Cvirus, hepatitis D virus, and Hepatitis E virus, such as (cell type tosupport Hepatitis infection), and can serve as antiviral agents for thetreatment and prevent of diseases associated with infection with ahepatits virus, for example hepatitis A virus, hepatitis B virus,hepatitis C virus, hepatitis D virus, and Hepatitis E virus, as well asother viral species that infect the liver.

Without wishing to be limited by theory, it is believed that thesubstituted aminothiazoles of the disclosure can ameliorate, abate,otherwise cause to be controlled, diseases associated unregulated cellgrowth. In addition, and also without wishing to be limited by theory,it is believed that the substituted aminothiazoles of the disclosure canameliorate, abate, otherwise cause to be controlled, diseases associatedwith infection of the liver with a virus.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present teachings also consistessentially of, or consist of, the recited components, and that theprocesses of the present teachings also consist essentially of, orconsist of, the recited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components and can be selected from a groupconsisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa)unless specifically stated otherwise. In addition, where the use of theterm “about” is before a quantitative value, the present teachings alsoinclude the specific quantitative value itself, unless specificallystated otherwise.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present teachings remainoperable. Moreover, two or more steps or actions can be conductedsimultaneously.

As used herein, the term “halogen” shall mean chlorine, bromine,fluorine and iodine.

As used herein, unless otherwise noted, “alkyl” and/or “aliphatic”whether used alone or as part of a substituent group refers to straightand branched carbon chains having 1 to 20 carbon atoms or any numberwithin this range, for example 1 to 6 carbon atoms or 1 to 4 carbonatoms.

Designated numbers of carbon atoms (e.g. C₁₋₆) shall refer independentlyto the number of carbon atoms in an alkyl moiety or to the alkyl portionof a large alkyl-containing substituent. Non-limiting examples of alkylgroups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, and the like. Alkyl groups can be optionallysubstituted. Non-limiting examples of substituted alkyl groups includehydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl,1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, andthe like. In substituent groups with multiple alkyl groups such as(C₁₋₆alkyl)₂amino, the alkyl groups may be the same or different.

As used herein, the terms “alkenyl” and “alkynyl” groups, whether usedalone or as part of a substituent group, refer to straight and branchedcarbon chains having 2 or more carbon atoms, preferably 2 to 20, whereinan alkenyl chain has at least one double bond in the chain and analkynyl chain has at least one triple bond in the chain. Alkenyl andalkynyl groups can be optionally substituted. Nonlimiting examples ofalkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, andthe like. Nonlimiting examples of substituted alkenyl groups include2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-1-yl,7-hydroxy-7-methyloct-4-en-2-yl, 7-hydroxy-7-methyloct-3,5-dien-2-yl,and the like. Nonlimiting examples of alkynyl groups include ethynyl,prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl.Nonlimiting examples of substituted alkynyl groups include,5-hydroxy-5-methylhex-3-ynyl, 6-hydroxy-6-methylhept-3-yn-2-yl,5-hydroxy-5-ethylhept-3-ynyl, and the like.

As used herein, “cycloalkyl,” whether used alone or as part of anothergroup, refers to a non-aromatic carbon-containing ring includingcyclized alkyl, alkenyl, and alkynyl groups, e.g., having from 3 to 14ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms,or even 3 to 4 ring carbon atoms, and optionally containing one or more(e.g., 1, 2, or 3) double or triple bond. Cycloalkyl groups can bemonocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fusedbridge, and/or spiro ring systems), wherein the carbon atoms are locatedinside or outside of the ring system. any suitable ring position of thecycloalkyl group can be covalently linked to the defined chemicalstructure. Cycloalkyl rings can be optionally substituted. Nonlimitingexamples of cycloalkyl groups include: cyclopropyl,2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl,2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl,decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl,4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl,octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl,decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, anddodecahydro-1H-fluorenyl. The term “cycloalkyl” also includescarbocyclic rings which are bicyclic hydrocarbon rings, non-limitingexamples of which include, bicyclo-[2.1.1]hexanyl,bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl,1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, andbicyclo[3.3.3]undecanyl.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl groupsinclude perhaloalkyl groups, wherein all hydrogens or an alkyl grouphave been replaced with halogens (e.g., —CF₃, —CF₂CF₃). Haloalkyl groupscan optionally be substituted with one or more substitutents in additionto halogen. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl groups.

The term “alkoxy” refers to the group —O-alkyl, wherein the alkyl groupis as defined above. Alkoxy groups optionally may be substituted. Theterm C₃-C₆ cyclic alkoxy refers to a ring containing 3 to 6 carbon atomsand at least one oxygen atom (e.g., tetrahydrofuran,tetrahydro-2H-pyran). C₃-C₆ cyclic alkoxy groups optionally may besubstituted.

The term “aryl,” wherein used alone or as part of another group, isdefined herein as a an unsaturated, aromatic monocyclic ring of 6 carbonmembers or to an unsaturated, aromatic polycyclic ring of from 10 to 14carbon members. Aryl rings can be, for example, phenyl or naphthyl ringeach optionally substituted with one or more moieties capable ofreplacing one or more hydrogen atoms. Non-limiting examples of arylgroups include: phenyl, naphthylen-1-yl, naphthylen-2-yl,4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl,2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl,3-methoxyphenyl, 8-hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-1-yl,and 6-cyano-naphthylen-1-yl. Aryl groups also include, for example,phenyl or naphthyl rings fused with one or more saturated or partiallysaturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl,indanyl), which can be substituted at one or more carbon atoms of thearomatic and/or saturated or partially saturated rings.

The term “arylalkyl” or “aralykyl” refers to the group -alkyl-aryl,where the alkyl and aryl groups are as defined herein. Aralkyl groups ofthe present invention are optionally substituted. Examples of arylalkylgroups include, for example, benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

The terms “heterocyclic” and/or “heterocycle” and/or “heterocylyl,”whether used alone or as part of another group, are defined herein asone or more ring having from 3 to 20 atoms wherein at least one atom inat least one ring is a heteroatom selected from nitrogen (N), oxygen(O), or sulfur (S), and wherein further the ring that includes theheteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g.,indolinyl, tetrahydroquinolinyl, chromaryl). Exemplary heterocyclegroups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Oneor more N or S atoms in a heterocycle group can be oxidized. Heterocyclegroups can be optionally substituted.

Non-limiting examples of heterocyclic units having a single ringinclude: diazirinyl, aziridinyl, urazolyl, azetininyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl,isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl,hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl,piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl(valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole,and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclicunits having 2 or more rings include: hexahydro-1H-pyrrolizinyl,3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl,3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl,chromanyl, isochromanyl, indolinyl, isoindolinyl, anddecahydro-1H-cycloocta[b]pyrrolyl.

The term “heteroaryl,” whether used alone or as part of another group,is defined herein as one or more rings having from 5 to 20 atoms whereinat least one atom in at least one ring is a heteroatom chosen fromnitrogen (N), oxygen (O), or sulfur (S), and wherein further at leastone of the rings that includes a heteroatom is aromatic. In heteroarylgroups that include 2 or more fused rings, the non-heteroatom bearingring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) oraryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplaryheteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5ring heteroatoms independently selected from nitrogen (N), oxygen (O),or sulfur (S). One or more N or S atoms in a heteroaryl group can beoxidized. heteroaryl groups can be substituted. Non-limiting examples ofheteroaryl rings containing a single ring include: 1,2,3,4-tetrazolyl,[1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl,oxazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl,pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limitingexamples of heteroaryl rings containing 2 or more fused rings include:benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl,9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl,7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl,2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl,quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl,8-hydroxy-quinolinyl, and isoquinolinyl.

One non-limiting example of a heteroaryl group as described above isC₁-C₅ heteroaryl, which has 1 to 5 carbon ring atoms and at least oneadditional ring atom that is a heteroatom (preferably 1 to 4 additionalring atoms that are heteroatoms) independently selected from nitrogen(N), oxygen (O), or sulfur (S). Examples of C₁-C₅ heteroaryl include,but are not limited to, trizinyl, thiazol-2-yl, thiazol-4-yl,imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl,furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl.

Unless otherwise noted, when two substituents are taken together to forma ring having a specified number of ring atoms (e.g., R² and R³ takentogether with the nitrogen (N) to which they are attached to form a ringhaving from 3 to 7 ring members), the ring can have carbon atoms andoptionally one or more (e.g., 1 to 3) additional heteroatomsindependently selected from nitrogen (N), oxygen (O), or sulfur (S). Thering can be saturated or partially saturated and can be optionallysubstituted.

For the purposed of the present invention fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be considered to belong to the cyclic familycorresponding to the heteroatom containing ring. For example,1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclicunit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit. When a fused ring unit contains heteroatoms in both a saturatedand an aryl ring, the aryl ring will predominate and determine the typeof category to which the ring is assigned. For example,1,2,3,4-tetrahydro[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroarylunit.

Whenever a term or either of their prefix roots appear in a name of asubstituent the name is to be interpreted as including those limitationsprovided herein. For example, whenever the term “alkyl” or “aryl” oreither of their prefix roots appear in a name of a substituent (e.g.,arylalkyl, alkylamino) the name is to be interpreted as including thoselimitations given above for “alkyl” and “aryl.”

The term “substituted” is used throughout the specification. The term“substituted” is defined herein as a moiety, whether acyclic or cyclic,which has one or more hydrogen atoms replaced by a substituent orseveral (e.g., 1 to 10) substituents as defined herein below. Thesubstituents are capable of replacing one or two hydrogen atoms on twoadjacent carbons to form said substituent, new moiety or unit. forexample, a substituted unit that requires a single hydrogen atomreplacement includes halogen, hydroxyl, and the like. A two hydrogenatom replacement includes carbonyl, oximino, and the like. A twohydrogen atom replacement from adjacent carbon atoms includes epoxy, andthe like. The term “substituted” is used throughout the presentspecification to indicate that a moiety can have one or more of thehydrogen atoms replaced by a substitutent. When a moiety is described as“substituted” any number of the hydrogen atoms may be replaced. Forexample, difluoromethyl is a substituted C₁ alkyl; trifluoromethyl is asubstituted C₁ alkyl; 4-hydroxyphenyl is a substituted aromatic ring;(N,N-dimethyl-5-amino)octanyl is a substituted C₃ alkyl;3-guanidinopropyl is a substituted C₃ alkyl; and 2-carboxypyridinyl is asubstituted heteroaryl.

The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl,cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groupsdefined herein, whether used alone or as part of another group, can beoptionally substituted. Optionally substituted groups will be soindicated.

The following are non-limiting examples of substitutents which cansubstitute for hydrogen atoms on a moiety: halogen (chlorine (Cl),bromine (Br), fluorine (F) and iodine (I)), —CN, —NO₂, oxo (═O), —OR³,—SR³, —N(R³)₂, —NR³C(O)R³, —SO₂R³, —SO₂OR³, —SO₂N(R³)₂, —C(O)R³,—C(O)OR³, —C(O)N(R³)₂, C₁₋₈ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₁₄ cycloalkyl, aryl, heterocycle, orheteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, aryl, heterocycle, and heteroaryl groups isoptionally substituted with 1-10 (e.g., 1-6 or 1-4) groups selectedindependently from halogen, —CN, —NO₂, oxo, and R³; wherein R³, at eachoccurrence, independently is hydrogen, —OR⁴, —SR⁴, —C(O)R⁴, —C(O)OR⁴,—C(O)N(R⁴)₂, —SO₂R⁴, —S(O)₂OR⁴, —N(R⁴)₃, —NR⁴)₃, —NR⁴C(O) R⁴, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cycloalkyl (e.g.,C₃₋₆ cycloalkyl), aryl, heterocycle, or heteroaryl, or two R

units taken together with the atoms(s) to which they are bound form anoptionally substituted carbocycle or heterocycle wherein said carbocycleor heterocycle has 3 to 7 ring atoms; wherein R⁴, at each occurrence,independently is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, cycloalkyl (e.g., C₃₋₆ cycloalkyl), aryl, heterocycle, orheteroaryl, or two R⁴ units taken together with the atom(s) to whichthey are bound form an optionally substituted carbocycle or heterocyclewherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

In some embodiments, the substitutents are selected from

-   -   i) —OR⁵; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;    -   ii) —C(O)R⁶; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;    -   iii) —C(O)OR⁵; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;    -   iv) —C(O)N(R⁵); for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;    -   v) —N(R⁵)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);    -   vi) halogen: —F, —Cl, —Br, and —I;    -   vii) —CH_(c)X₈; wherein X is halogen, m is from 0 to 2, e+g=3;        for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   viii) —SO₂R⁵; for example, —SO₂H; —SO₂CH₃; —SO₂C₆H₆;    -   ix) C₁-C₆ linear, branched, or cyclic alkyl;    -   x) Cyano    -   xi) Nitro;    -   xii) N(R⁵)C(O)R⁵;    -   xiii) Oxo (═O);    -   xiv) Heterocycle; and    -   iv) Heteroaryl.        wherein each R⁵ is independently hydrogen, optionally        substituted C₁-C₆ linear or branched alkyl (e.g., optionally        substituted C₁-C₄ linear or branched alkyl), or optionally        substituted C₃-C₆ cycloalkyl (e.g. optionally substituted C₃-C₄        cycloalkyl); or two R⁵ units can be taken together to form a        ring comprising 3-7 ring atoms. In certain aspects, each R⁵ is        independently hydrogen, C₁-C₆ linear or branched alkyl        optionally substituted with halogen or c₃-C₆ cycloalkyl or C₃-C₆        cycloalkyl.

At various places in the p resent specification, substituents ofcompounds are disclosed in groups or in ranges. It is specificallyintended that the description include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclosedC₁, C₂, C₃, C₄, C₅, C₆, C₁-C₆, C₁-C₅, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅,C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆, alkyl.

For the purposes of the present invention the terms “compound,”“analog,” and “composition of matter” stand equally well for thesubstituted aminothiazoles described herein, including all enantiomericforms, diastereomeric forms, salts, and the like, and the terms“compounds,” “analog,” and “composition of matter” are usedinterchangeably throughout the present specification.

Compounds described herein can contain an asymmetric atom (also referredas a chiral center), and some of the compounds can contain one or moreasymmetric atoms or centers, which can thus give rise to optical isomers(enantiomers) and diastereomers. The present teachings and compoundsdisclosed herein include such enantiomers and diastereomers, as well asthe racemic and resolved, enantiomerically pure R and S stereoisomers,as well as other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof. Optical isomers can beobtained in pure form by standard procedures known to those skilled inthe art, which include, but are not limited to, diastereomeric saltformation, kinetic resolution, and asymmetric synthesis. The presentteachings also encompass cis and trans isomers of compounds containingalkenyl moieties (e.g., alkenes and imines). It is also understood thatthe present teachings encompass all possible regioisomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography.

Pharmaceutically acceptable salts of compounds of the present teachings,which can have an acidic moiety, can be formed using organic andinorganic bases. Both mono and polyanionic salts are contemplated,depending on the number of acidic hydrogens available for deprotonation.Suitable salts formed with bases include metal salts, such as alkalimetal or alkaline earth metal salts, for example sodium, potassium, ormagnesium salts; ammonia salts and organic amine salts, such as thoseformed with morpholine, thiomorpholine, piperidine, pyrrolidine, amono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-,di-, or trihydroxy lower alkylamine (e.g., mono-, di- ortriethanolamine). Specific non-limiting examples of inorganic basesinclude NaHCO₃, Na₂CO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs_(s)CO₃, LiOH, NaOH,KOH, NaH₂PO₄, Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed.Similarly, when a compound disclosed herein contains a basic moiety,salts can be formed using organic and inorganic acids. For example,salts can be formed from the following acids; acetic, propionic, lactic,benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic,dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic,hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric,oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic,sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well asother known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence (e.g., in N(R⁴)₂, each R⁴ may bethe same or different than the other). Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The terms “treat” and “treating” and “treatment” as used herein, referto partially or completely alleviating, inhibiting, ameliorating and/orrelieving a condition from which a patient is suspected to suffer.

As used herein, “therapeutically effective” and “effective dose” referto a substance or an amount that elicits a desirable biological activityor effect.

Except when noted, the terms “subject” or “patient” are usedinterchangeabaly and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryembodiment of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat may be associated with the targeted or suspected disease orcondition. These and other routine methods allow the clinician to selectpatients in need of therapy using the methods and compounds of thepresent invention

The Substituted Aminothiazoles

The compounds of the present invention are substituted aminothiazoles,and include all enantiomeric and diastereomeric forms andpharmaceutically accepted salts thereof having the formula:

Including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein:

-   -   R¹ is selected from a group consisting of hydrogen, C₁-C₉ linear        alkyl, isopropyl, cyclohexyl, bromine, cyano,

R² is selected from a group consisting of hydrogen, methyl, isopropyl,tert-butyl, benzyl, and

Ar¹ is selected from a group consisting of phenyl,

Ar² is selected from a group consisting of phenyl,

Compounds of the structures

are excluded from the novel compounds of formula (I).

The present invention is also directed toward novel methods of use ofcompounds of the structure

In some embodiments, R¹ is hydrogen.

In some embodiments, R¹ is C₁-C₉ linear alkyl

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is ethyl.

In some embodiments, R¹ is ethyl.

In some embodiments, R¹ is pentyl.

In some embodiments, R¹ is nonyl.

In some embodiments, R¹ is isopropyl.

In some embodiments, R¹ is cyclohexyl.

In some embodiments, R¹ is bromine.

In some embodiments, R¹ is cyano.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R² is hydrogen.

In some embodiments, R² is methyl.

In some embodiments, R² is isopropyl.

In some embodiments, R² is tert-butyl

In some embodiments, R² is benzyl

In some embodiments, R² is

In some embodiments, Ar¹ is phenyl.

In some embodiments, Ar¹ is

In some embodiments, Ar¹ is

In some embodiments, Ar¹ is

In some embodiments, Ar¹ is

In some embodiments, Ar¹ is

In some embodiments, Ar¹ is

In some embodiments, Ar¹ is

In some embodiments, Ar¹ is

In some embodiments, Ar² is phenyl.

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

In some embodiments, Ar² is

Exemplary embodiments include compounds having the formula (I) or apharmaceutically acceptable salt form thereof:

wherein non-limiting examples of R¹, R², Ar¹ and Ar² are defined hereinbelow in Table 1.

TABLE 1 Exemplary embodiments of compounds of the formula (I): Entry R¹R² Ar¹ Ar² 1 H H

2 H H Phenyl Phenyl 3 H H Phenyl

4 H H Phenyl

5 H H

6 H H

7 H H

8 H H

9 H H

10 H H

11 H H

12 H H

13 H H

14 H H

15 H H

16 H H

17 H H

18 H H

19 H H

20 H H

21 CH₃ H

22 CH₂CH₃ H

23 CH(CH₃)₂ H

24 CH₂(CH₃)₃CH₃ H

25 Cyclohexyl H

26 Nonyl H

27 Cyano H

28 H Isopropyl

29 H Methyl

30 H Benzyl

31 H

32 Br H

33

H

34

H

35

H

36

H

37

H

38

H

39

H

40 CO₂H H

41

H

42

43

H

44

H

45

H

46

H

47

H

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name N-(pyrazin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine.

For the purposes of demonstrating the manner in which the compounds ofthe present invention are named and referred to herein, the compoundhaving the formula:

has the chemical name(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl butyrate.

For the purposes of the present invention, a compound depicted by theracemic formula, will stand equally well for either of the twoenantiomers or mixtures thereof, or in the case where a second chiralcenter is present, all diastereomers.

In all of the embodiments provided herein, examples of suitable optionalsubstituents are not intended to limit the scope of the claimedinvention. The compounds of the invention may contain any of thesubstituents, or combinations of substitutents, provided herein.

PROCESS

The present invention further relates to a process for preparing thecompounds of the present invention.

Compounds of the present teachings can be prepared in accordance withthe procedures outlined herein, from commercially available startingmaterials, compounds known in the literature, or readily preparedintermediates, by employing standard synthetic methods and proceduresknown to those skilled in the art of organic chemistry. Standardsynthetic methods and procedures for the preparation of organicmolecules and functional group transformations and manipulations can bereadily obtained from the relevant scientific literature or fromstandard textbooks in the field. It will be appreciated that wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions can vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art b routine optimization procedures. Those skilled in the art oforganic synthesis will recognize that the nature and order of thesynthetic steps presented can be varied for the purpose of optimizingthe formation of the compounds described herein.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), mass spectrometry, or by chromatography such as highpressure liquid chromatography (HPLC), gas chromatography (GC),gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection ofvarious chemical groups. The need for protection and deprotection andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene et al., Protective Groups in OrganicSynthesis, 2d. Ed. (Wiley & sons, 1991), the entire disclosure of whichis incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out insuitable solvents which can be readily selected by one skilled in theart of organic synthesis. Suitable solvents typically are substantiallynonreactive with the reactants, intermediates, and/or products at thetemperatures at which the reactions are carried out, i.e., temperaturesthat can range from the solvent's freezing temperature to the solvent'sboiling temperature. A given reaction can be carried out in one solventor a mixture of more than one solvent. Depending on the particularreaction step, suitable solvents for a particular reaction step can beselected.

The Examples provided below provide representative methods for preparingexemplary compounds of the present invention. The skilled practitionerwill know how to substitute the appropriate reagents, starting materialsand purification methods known to those skilled in the art, in order toprepare the compounds of the present invention.

¹H NMR spectra were recorded on a 300 MHz INOVA VARIAN spectrometer.Chemical shifts values are given in ppm and referred as the internalstandard to TMS (tetramethylsilane). The peak patterns are indicated asfollows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multipletand dd, doublet of doublets. The coupling constants (J) are reported inHertz (Hz). Mass Spectra were obtained on a 1200 Aligent LC-MSspectrometer (ES-API, Positive). Silica gel column chromatography wasperformed over silica gel 100-200 mesh using the solvent systemsdescribed herein herein.

The examples provide methods for preparing representative compounds offormula (I). The skilled practitioner will know how to substitute theappropriate reagents, starting materials and purification methods knownto those skilled in the art, in order to prepare additional compounds ofthe present invention.

EXAMPLE 1

Synthesis of 1-(pyrimidin-2-yl)thiourea:

To a suspension of potassium thiocyanate (3.31 g, 34.0 mmol) inanhydrous ethyl acetate (30 mL) at 0° C. under the argon atmosphere, wasadded dropwise a solution of fluorenylmethyloxy-carbonyl chloride (8.00g, 30.9 mmol) in anhydrous ethyl acetate (30 mL). After addition, thereaction mixture was stirred at room temperature for 24 hours. Then, itwas concentrated and purified through silica gel column chromatography(dichloromethan:hexanes=40:60) to afford 5.00 g of pure productO-((9H-fluoren-9-yl)methyl) carbonisothiocyanatidate as colorless oil.

A reaction mixture of O-((9H-fluoren-9-yl)methyl)carbonisothiocyanatidate (5.00 g, 17.8 mmol) and pyrimidin-2-amine (1.61g, 16.9 mmol) in toluene (80 mL) was refluxed for 4 hours. then, it wasfiltered and washed with toluene to give 6.00 g of product1-Fmoc-3-(pyrimidin-2-yl)thiourea as white solid, which was directlyused in the next step without further purification.

To a stirred suspension of 1-Fmoc-3-(pyrimidin-2-yl)thiourea (6.00 g,15.9 mmol) in dichloromethane (120 mL), was added piperidine (24 mL).The reaction mixture was stirred at room temperature for 20 hours, andthen filtered and washed with dichloromethane. The crude product wasslurried in water (50 mL) for 10 minutes, filtered, washed with waterand dried under the vacuum to afforded 2.35 g of pure product1-(pyrimidin-2-yl)thiourea as white solid. ¹H NMR (300 MHz, DMSO-d₆): δ10.57 (s, 1H, NH), 10.20 (s, 1H, NH), 9.13 (s, 1H, NH), 8.63 (d, J=4.8Hz, 2H, CH

), 7.14 (t, J=5.1 Hz, 1H, CH

).

EXAMPLE 2

Synthesis of 1-(pyrazin-2-yl)thiourea

1-(pyrazin-2-yl)thiourea was synthesized from pyrazin-2-ylamine in thesame manner as Example 1 to provide the product as a white solid. ¹H NMR(300 MHz, DMSO-d₆): δ 10.83 (s, 1H, NH), 9.94 (s, 1H, NH), 9.08 (s, 1H,NH), 8.52 (s, 1H, CH

), 8.23 (s, 2H, CH

).

EXAMPLE 3

Synthesis of 1-(pyrimidin-4-yl)thiourea.

1-(pyrimidin-4-yl)thiourea was synthesized from pyrimidin-4-ylamine inthe same manner as Example 1 to provide the produce as a white solid. ¹HNMR (300 MHz, DMSO-d₆): δ 10.83 (s, 1H, NH), 10.28 (s, 1H, NH), 9.29 (s,1H, NH), 8.78 (d, J=0.6 Hz, 1H, CH

), 8.54 (d, J=6.0 Hz, 1H, CH

), 7.14 (dd, J=5.7, 1.2 Hz, 1, CH

).

EXAMPLE 4

Synthesis of 1-(5-chloropyrimidin-2-yl)thiourea.

1-(5-chloropyrimidin-2-yl)thiourea was synthesized from5-chloro-pyrimidin-2-ylamine in the same manner as Example 1 to providethe product as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 10.88 (s, 1H,NH), 9.90 (s, 1H, NH), 9.20 (s, 1H, NH), 8.72 (s, 2H, CH

).

EXAMPLE 5

Synthesis of 1-(5-bromopyrimidin-2-yl)thiourea.

1-(5-bromopyrimidin-2-yl)thiourea was synthesized from5-bromo-pyrimidin-2-ylamine in the same manner as Example 1 to providethe product as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 10.85 (s, 1H,NH), 9.89 (s, 1H, NH), 9.21 (s, 1H, NH), 8.77 (s, 2H, CH

).

EXAMPLE 6

Synthesis of 1-(4-(trifluoromethyl)pyrimidin-2-yl)thiourea.

1-(4-(trifluoromethyl)pyrimidin-2-yl)thiourea was synthesized from4-trifluoromethyl-pyrimidin-2-ylamine in the same manner as Example 1 toprovide the product. ¹H NMR (300 MHz, DMSO-d₆): δ 9.85 (s, 1H, NH), 9.33(s, 1H, NH), 8.97 (d, J=5.1 Hz, 1H, CH

), 7.61 (d, J=4.8 Hz, 1H, CH

).

EXAMPLE 7

Synthesis of 1-(4-methylpyrimidin-2-yl)thiourea.

Benzoyl chloride (1.74 mL, 15 mmol) was added dropwise to a solution ofammonium thiocyanate (1.90 g, 25 mmol) in dry acetone (20 mL) at roomtemperature. It was heated to reflux for 15 minutes, and then treatedwith 4-methylpyrimidin-2-amine (1.09 g, 10 mmol). Refluxing wascontinued for 30 minutes. After cooling down, the reaction mixture waspoured onto ice and stirred for 30 minutes. The precipitate wascollected by filtration, washed with water, and then hydrolyzed in 2Nsodium hydroxide (30 mL) at 80° C. for 30 minutes. It was cooled to roomtemperature and poured into ice-cold 6 M HCl (20 mL). The pH wasadjusted to 8˜9 with powder sodium carbonate. The crude product wascollected by filtration and washed with water. It was further slurriedin dichloromethane and filtered to give 340 mg of compound1-(4-methylpyrimidin-2-yl)thiourea as white solid. ¹H NMR (300 MHz,DMSO-d₆): δ 10.39 (s, 1H, NH), 10.27 (s, 1H, NH), 9.09 (s, 1H, NH), 8.46(d, J=5.1 Hz, 1H, CH

), 7.03 (d, J=5.1 Hz, 1H, CH

), 2.40 (s, 3H, ArCH₃).

EXAMPLE 7

Synthesis of 1-(6-methylbenzo[d]thiazol-2-yl)thiourea.

Synthesis of 1-(6-methylbenzo[d]thiazol-2-yl)thiourea was synthesizedfrom 6-methyl-benzothiazol-2-ylamine in the same manner as Example 7 toprovide the product white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.73 (s,1H, NH), 9.06 (s, 2H, NH₂), 7.69 (s, 1H, CH

), 7.56 (d, J=7.8 Hz, 1H, CH

), 7.20 (d, J=7.5 Hz, 1H, CH

), 2.37 (s, 3H, ArCH₃).

EXAMPLE 8

Synthesis of 1-(pyrimidin-2-yl)thiourea.

To a suspension of potassium thiocyanate (4.28 g, 44.0 mmol) inanhydrous ethyl acetate (EtOAc, 50 mL) at 0° C. under the argonatmosphere, was added dropwise a solution of fluorenylmethyloxy-carbonylchloride (Fmoc-Cl, 10.35 g, 40.0 mmol) in anhydrous ethyl acetate (50mL). After addition, the reaction mixture was stirred at roomtemperature for 24 hours. The reaction mixture was diluted with hexanes(100 mL), then filtered through a silica gel pad and washed with amixture of dichloromethane and hexanes (25:75, 200 mL). The filtrate wasconcentrated to give the crude O-((9H-fluoren-9-yl)methyl)carbonisothiocyanatidate as light-yellow oil, which was dissolved intoluene (100 mL), followed by addition of pyrimidin-2-amine (3.62 g,38.0 mmol). It was refluxed for 4 hours, filtered and washed withtoluene (100 mL) to afford 1-Fmoc-3-(pyrimidin-2-yl)thiourea, which wassuspended in dichloromethane (100 mL) and treated with piperidine (24mL). After stirred at room temperature for 12 hours, the mixture wasfiltered and washed with dichloromethane (100 mL) then water (100 mL).The solid was dried under the vacuum to afforded 4.45 g of pure product1-(pyrimidin-2-yl)thiourea as light-brown solid.

EXAMPLE 8

Synthesis of 1-(pyridin-2-yl)propan-1-one.

To a stirred solution of 2-cyanopyridine (1.04 g. 10 mmol) in anhydrousdiethyl ether (20 mL) at <−15° C. under argon atmosphere, was addedslowly isobutylmagnesium bromide (2M in diethyl ether, 60 mL, 12 mmol).After addition, the reaction mixture was stirred at this temperature for1 hour, and then allowed to warm up to room temperature over 3 hours. Itwas quenched with 2N HCl (6 mL) at 0° C. and stirred for another 15minutes. The pH was adjusted to 8˜9 with 2N NaOH. the mixture wasdiluted with water (15 mL) and extracted with ethyl acetate (30 mL×3).The combined organic layer wad dried over Na₂SO₄, concentrated andpurified through silica gel column chromatography (ethylacetate:hexanes=4:96 to 16:84) to afford 1.40 g product1-(pyridin-2-yl)propan-1-one as colorless oil. ¹H NMR (300 MHz, CDCl₆):δ 8.68 (dt, J=4.2, 0.9 Hz, 1H, CH

), 8.04 (d, J=8.1 Hz, 1H, CH

), 7.83 (dt, J=7.5, 1.8 Hz, 1H, CH

), 7.48-7,.43 (m, 1H, CH

), 3.11 (d, J=6.6 Hz, 2H, CH₂CO), 2.34-2.30 (m, 1H, CH), 1.00 (d, J=6.6Hz, 6H, C(CH₃)₂). MS:MH⁺=164.

EXAMPLE 9

Synthesis of 1-(3,5-dimethylpyridin-2-yl)ethanone.

1-(3,5-dimethylpyridin-2-yl)ethanone was synthesized from3,5-dimethylpyridine-2-carbonitrile and methylmagnesium bromide in thesame manner as Example 8 to provide the product as a colorless oil. ¹HNMR (300 MHz, CDCl₃): δ 8.33 (d, J=0.9 Hz, 1H, CH

), 7.37 (d, J=1.5 Hz, 1H, CH

), 2.69 (s, 3H, CH₃), 2.56 (s, 3H, CH₃), 2.36 (s, 3H, CH₃CO).MS:MH⁺=150.

EXAMPLE 10

Synthesis of 1-(6-methoxypyridin-2-yl)ethanone.

1-(6-methoxypyridin-2-yl)ethanone was synthesized from6-Methoxy-pyridine-2-carbonitrile and methylmagnesium bromide in thesame manner as Example 8 to provide the product as a solid. ¹H NMR (300MHz, CDCl₃): δ 7.72-7.62 (m, 2H, CH

), 6.93 (dd, J=8.1, 0.9 Hz, 1H, CH

), 4.00 (s, 3H, CH₃OAr), 2.69 (s, 3H, CH₃CO). MS:MH⁺=152.

EXAMPLE 11

Synthesis of 1-(quinolin-2-yl)ethanone.

1-(quinolin-2-yl)ethanone was synthesized from Quinoline-2-carbonitrileand methylmagnesium bromide in the same manner as Example 8 to providethe product at a white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.27 (d, J=8.4Hz, 1H, CH

), 8.20 (d, J=8.7 Hz, 1H, CH

), 8.13 (d, J=8.7 Hz, 1H, CH

), 7.87 (d, J=8.4 Hz, 1H, CH

), 7.82-7.76 (m, 1H, CH

), 7.68-7.62 (m, 1H, CH

), 2.88 (s, 3H, CH₃CO). MS: MH⁺=172.

EXAMPLE 12

Synthesis of 1-(pyridin-2-yl)propan-1-one.

1-(pyridin-2-yl)propan-1-one was synthesized frompyridine-2-carbonitrile and ethylmagnesium bromide in the same manner asExample 8 to provide the product as a light-yellow oil. ¹H NMR (300 MHz,CDCl₃): δ 8.68 (dt, J=4.8, 0.9 Hz, 1H, CH

), 8.05 (dt, J=8.1, 1.2 Hz, 1H, CH

), 7,83 (dt, J=7.5, 1.8 Hz, 1H, CH

), 7.49-7.44 (m, 1H, CH

), 3.25 (q, J=7.5 Hz, 2H, CH₂CO), 1.22 (t, J=7.5 Hz, 3H, CH₃). MS:MH⁺=136.

EXAMPLE 13

Synthesis of 1-(pyridin-2-yl)butan-1-one.

1-(pyridin-2-yl)butan-1-one was synthesized from Pyridine-2-carbonitrileand propylmagnesium bromide in the same manner as Example 8 to providethe product as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 8.68 (dq,J=5.1, 0.9 Hz, 1H, CH

), 8.04 (dt, J=8.1, 1.2 Hz, 1H, CH

), 7.83 (dt, J=7.5, 1.8 Hz, 1H, CH

), 7.48-7.44 (m, 1H, CH

), 3.20 (t, J=7.5 Hz, 2H, CH₂CO), 1.81-1.74 (m, 2H, CH₂), 1.02 (t, J=7.5Hz, 3H, CH₃). MS: MH⁺=150.

EXAMPLE 14

Synthesis of 1-(pyridin-2-yl)heptan-1-one.

1-(pyridin-2-yl)heptan-1-one was synthesized frompyridine-2-carbonitrile and hexyl magnesium bromide in the same manneras Example 8 to provide the product as a colorless oil. ¹H NMR (300 MHz,CDCl₃): δ 8.68 (dq, J=4.8, 0.9 Hz, 1H, CH

), 8.04 (dt, J=8.1, 0.9 Hz, 1H, CH

), 7.83 (dt, J=7.5, 1.8 Hz, 1H, CH

, 7.48-7.44 (m, 1H, CH

), 3.21 (t, J=7.5 Hz, 2H, CH₂CO), 1.76-1.68 (m, 2H, CH₂), 1.42-1.26 (m,6H, 3×CH₂), 0.89 (t, J=7.2 Hz, 3H, CH₃). MS: MH⁺=192.

EXAMPLE 15

Synthesis of 2-cyclohexyl-1-(pyridin-2-yl)ethanone.

2-Cyclohexyl-1-(pyridin-2-yl)ethanone was synthesized frompyridine-2-carbonitrile and cyclohexylmethyl magnesium bromide in thesame manner as example 8 to provide the product as a colorless oil. ¹HNMR. (300 MHz, CDCl₃): δ 8.68 (dt, J=3.9, 0.6 Hz, 1H, CH

), 8.03 (d, J=8.1 Hz, 1H, CH

), 7.83 (dt, J=7.8, 1.8 Hz, 1H, CH

), 7.48-7.43 (m, 1H, CH

), 3.10 (d, J=7.2 Hz, 2H, CH₂CO), 2.04-2.00 (m, 1H, CH), 1.78-1.02 (m,10H, 5×CH₂). MS: MH⁺=204.

EXAMPLE 16

Synthesis of 1-(pyridin-2-yl)undecan-1-one.

1-(pyridin-2-yl)undecan-1-one was synthesized frompyridine-2-carbonitrile and undecanyl magnesium bromide in the samemanner as example 8 to provide the product as a colorless oil. ¹H NMR(300 MHz, CDCl₃): δ 8.68 (dq, J=4.8, 0.9 Hz, 1H, CH

), 8.04 (dt, J=8.1, 1.2 Hz, 1H, CH

), 7.83 (dt, J=7.5, 1.8 Hz, 1H, CH

), 7.48-7.43 (m, 1H, CH

), 3.21 (t, J=7.5 Hz, 2H, CH₂CO), 1.75-1.68 (m, 2H, CH₂), 1.35-1.23 (m,14H, 7×CH₂), 0.88 (t, J=6.9 Hz, 3H, CH₃). MS: MH⁺=248.

EXAMPLE 17

Synthesis of ethyl 3-(7-methylpyridin-2-yl)-3-oxopropanoate.

A reaction mixture of 6-methylpicolinic acid (1.0 g, 7.3 mmol) and conc.sulfuric acid (˜98%, 0.6 mL) in ethanol (40 mL) was refluxed for 24hours. The extra ethanol was evaporated, followed by addition of water(20 mL) at 0° C. The pH was adjusted to 9was sodium bicarbonate powder.Then the mixture was extracted with ethyl acetate (30 mL×3), and thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated to afford 1.20 g of ethyl 6-methylpicolinate as a colorlessoil. MS: MH⁺=166.

A solution of anhydrous ethyl acetate (1 mL, 9.9 mmol) in toluene (10mL), was treated with sodium ethoxide (449 mg, 6.6 mg) at roomtemperature. The mixture was stirred under argon atmosphere for 1 hour,and then, ethyl 6-methylpicolinate (499 mg, 3.3 mmol) was added. Thereaction mixture was heated to reflux for 20 hours. After cooling toroom temperature, it was acidified (pH=6) with acetic acid, followed byaddition of water (20 mL) and extracted with ethyl acetate (20 mL×3).The combined organic layer was dried over anhydrous sodium sulfate,concentrated and purified through silica gel column chromatography(ethyl acetate:hexanes=10:90 to 20:80) to afford 440 mg of compoundethyl 3-(6-methylpyridin-2-yl)-3-oxopropanoate as light-yellow oil. ¹HNMR (300 MHz, CDCl₃): δ 7.87 (d, J=7.8 Hz, 1H, CH

), 7.72 (t, J=7.8 Hz, 1H, CH_(at)), 7.33 (d, J=7.5 Hz, 1H, CH

), 4.25-4.16 (m, 4H, 2×CH₂), 2.59 (s, 3H, ArCH₃), 1.24 5, J=7.2 Hz, 3H,CH₃). MS: MH⁺=208.

EXAMPLE 18

Synthesis of ethyl 3-(4-methylpyridin-2-yl)-3-oxopropanoate.

Ethyl 3-(4-methylpyridin-2-yl)-3-oxopropanoate was synthesized from4-methyl-pyridine-2-carboxylic acid in the same manner as Example 17 toprovide the product as a light yellow oil. ¹H NMR (300 MHz, CDCl₃): δ8.52 (d, J=5.1 Hz, 1H, CH

), 7.90 (d, J=0.6 Hz, 1H, CH

), 7.30 (dd, J=5.1, 0.9 Hz, 1H, CH

), 4.23-4.16 (m, 4H, 2×CH₂), 2.43 (s, 3H, ArCH₃), 1.24 (t, J=7.2 Hz, 3H,CH₃). MS; MH⁺=208.

EXAMPLE 19

Synthesis of 2-bromo-1-(pyridin-2-yl)ethanone hydrobromide.

To a solution of 2-acetylpyridine (2.42 g, 20 mmol) in a mixture of 48%hydrobromic acid (2.26 mL, 20 mmol) and acetic acid (22 mL) at 0° C. wasadded dropwise bromine (1.13 mL, 22 mmol). The reaction mixture wasstirred at room temperature for 1 hour, and then 75° C. for 3 hours.After cooling to room temperature, it was diluted with tetrahydrofuran(25 mL) and stirred overnight. The product was collected by filtration,washed with tetrahydrofuran and dried under vacuum. 5.38 g of2-bromo-1-(pyridin-2-yl)ethanone hydrobromide was afforded as whitesolid.

EXAMPLE 20

Synthesis of 4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

A reaction mixture of 2-bromo-1-(pyridin-2-yl) ethanone hydrobromide(1.69 g, 6 mmol), 1-(pyrimidin-2-yl)thiourea (0.93 g, 6 mmol), andtriethylamine (2.1 mL, 15 mmol) in ethanol (30 mL) was refluxed for 1hour under argon atmosphere. After cooling to room temperature, thereaction mixture was quenched with water 100 mL) and stirred for another2 hours. The crude product was collected by filtration and was furtherpurified by recrystallization in methanol. 1.14 g of compound4-(pyridin-2-yl)-N-(pyrimidin-2yl)thiazol-2-amine was afforded as whitesolid. ¹H NMR (500 MHz, DMSO-d₆): δ 11.88 (s, 1H, NH), 8.67 (d, J=5.0Hz, 2H, CH

), 8.61-8.59 (m, 1H, CH

), 7.99 (d, J=8.0 Hz, 1H, CH

), 7.89 (dt, J=7.5, 1.5 Hz, 1H, CH

), 7.75 (s, 1H, CH

), 7.33-7.31 (m, 1H, CH

), 7.06 (t, J=5.0 Hz, 1H, CH

). MS: MH⁺=256. 4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine couldbe further converted to the HCl salt using the following procedure: Asuspension of 4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (102mg, 0.4 mmol) in methanol (10 mL) was treated 4 M HCl solution (in1,4-dioxane, 1 mL). Then, it was heated to reflux and the reactionmixture became a clear solution. The solvent was removed by evaporationand the given residue was further purified by recrystallization in ethylacetate to afford 130 mg of HCl salt. ³H NMR (300 MHz, DMSO-d₆): δ8.71-8.67 (m, 3H, CH

), 8.33-8.24 (m, 3H, CH

), 7.71-7.67 (m, 1H, CH

), 7.09 (t, J=5.1 Hz, 1H, CH

). MS: MH⁺=256.

EXAMPLE 21

Synthesis of N,4-diphenylthiazol-2-amine.

N,4-diphenylthiazol-2-amine was synthesized from2-bromo-1-phenyl-ethanone and phenyl-thiourea in the same manner asExample 20 to provide the product as a light-yellow solid. ³H NMR (300MHz, CDCl₃): δ 7.88-7.84 (m, 2H, CH

), 7.55 (s, 1H, NH), 7.43-7.28 (m, 7H, CH

), 7.10-7.05 (m, 1H, CH

), 6.83 (d, J=1.8 Hz, 1H, CH

). MS: MH⁺=253.

EXAMPLE 22

Synthesis of N-phenyl-4-(pyridin-2-yl)thiazol-2-amine.

N-phenyl-4-(pyridin-2-yl)thiazol-2-amine was synthesized from2-bromo-1-pyridin-2-yl-ethanone and phenyl-thiourea in the same manneras Example 20 to provide the product as a light-yellow solid. ¹NMR (300MHz, CDCl₃): δ 8.62-8.60 (m, 1H, CH

), 8.00 (dt, J=8.1, 1.2 Hz, 1H, CH

), 7.75 (dt, J=8.1, 2.1 Hz, 1H, CH

), 7.44-7.34 (m, 6H, 5×CH

and NH overlapped), 7.23-7.18 (m, 1H, CH

), 7.11-7.06 (m, 1H, CH

). MS: MH⁺=254.

EXAMPLE 23

Synthesis of 4-phenyl-N-(pyrimidin-2-yl)thiazol-2-amine.

4-Phenyl-N-(pyrimidin-2-yl)thiazol-2-amine was synthesized from2-bromo-2-phenyl-ethanone and pyrimidin-2-yl-thiourea in the same manneras Example 20 to provide the product as a white solid. ¹H NMR (300 MHz,DMSO-d₆): δ 11.80 (s, 1H, NH), 8.63 (d, J=5.1 Hz, 2H, DH

), 7.92-7.89 (m, 2H, CH

), 7.52 (s, 1H, CH

), 7.42-7.38 (m, 2H, CH

) 7.31-7.29 (m, 1H, CH

), 7.03 (t, J=5.1 Hz, 1H, CH

). MS: MH⁺=255.

EXAMPLE 24

Synthesis of N,4-di(pyridin-2-yl)thiazol-2-amine.

N,4-di(pyridin-2-yl)thiazol-2-amine was synthesized from2-bromo-1-pyridin-2-yl-ethanone and pyridin-2-yl-thiourea in the samemanner as Example 20 to provide the product as a white solid. ¹H NMR(500 MHz, DMSO-d₆): δ 11.45 (s, 1H, NH), 8.60 (d, J=4.5 Hz, 1H, CH

), 8.32 (dd, J=5.5, 2.0 Hz, 1H, CH

), 7.97 (d, J=8.0 Hz, 1H, CH

), 7.88 (dt, J=8.0, 2.0 Hz, 1H, Ch_(at)), 7.75-7.71 (m, 1H, CH_(at)),7.65 (s, 1H, CH_(at)), 7.33-7.30 (m, 1H, CH_(at)), 7.11 (d, J=8.5 Hz,1H, CH_(at)), 6.96-6.93 (m, 1H, CH

). MS: MH⁺=255.

EXAMPLE 25

Synthesis of 4-(pyridin-3-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

4-(pyridin-3-yl)-N-(pyrimidin-2-yl)thiazol-2-amine was synthesized from2-bromo-1-pyridin-3-yl-ethanone and pyrimidin-2-yl-thiourea in the samemanner as Example 20 to provide the product as a gray solid. ¹H NMR (300MHz, DMSO-d₆): δ 11.93 (s, 1H, NH), 9.14-9.13 (M, 1H, CH

), 8.65 (d, J=4.8 Hz, 2H, CH

), 8.51 (dd, J=5.1, 1.8 Hz, 1H, Ch

), 8.25-8.21 (m, 1H, CH

), 7.70 (s, 1H, CH

), 7.46-7.42 (m, 1H, CH

), 7.04 (t, J=4.8 Hz, 1H, CH

). MS: MH⁺=256.

EXAMPLE 26

Synthesis of 4-(pyridin-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

4-(pyridin-4-yl)N-(pyrimidin-2-yl)thiazol-2-amine was synthesized from2-bromo-1-pyridin-4-yl-ethanone and pyrimidin-2-yl-thiourea in the samemanner as Example 20 to provide the product as a gray solid. ¹H NMR (300MHz, DMSO-d₆): δ 11.93 (s, 1H, NH), 8.65 (d, J=4.8 Hz, 2H CH_(at)), 8.59(dd, J=4.8 1.5 Hz, 2H, CH

), 7.89 (s, 1H, CH

), 7.85-7.83 (m, 2H, CH_(at)), 7.05 (t, J=4.8 Hz, 1H, CH

). MS: MH⁺=256.

EXAMPLE 27

Synthesis of N-(pyrazin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine.

N-(pyrazin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine was synthesized from2-bromo-1-pyridin-2-yl-ethanone and pyrimidin-2-yl-thiourea in the samemanner as Example 20 to provide the product as a brown solid. ¹H NMR(300 MHz, DMSO-d₆): δ 11.87 (s, 1H, NH), 8.60-8.57 (m, 1H, CH

), 8.51 (d, J=1.5 Hz, 1H, CH

), 8.32 (dd, J=3.0, 1.5 Hz, 1H, CH

), 8.13 (d, J=24 Hz, 1H, CH

), 7.96 (dt, J=7.8, 1.2 Hz, 1H, CH

), 7.87 (dt, J=7.8, 1.8 Hz, 1H, CH

), 7.73 (s, 1H, CH

), 7.33-7.29 (m, 1H, CH

). MS: MH⁺=256.

EXAMPLE 28

Synthesis of 4-(pyridin-2-yl)-N-(pyrimidin-4-yl)thiazol-2-amine.

4-(pyridin-2-yl)-N-(pyrimidin-4-yl)thiazol-2-amine was synthesized from2-bromo-1-pyridin-2-yl-ethanone and pyrimidin-4-yl-thiourea ion the samemanner as Example 20 to provide the product as a brown solid. ¹H NMR(300 MHz, DMSO-d₆): δ 11.91 (s, 1H, NH), 8.84 (d, J=0.9 Hz, 1H, CH

), 860-8.57 (m, 1H, CH

), 8.46 (d, J=6.0 Hz, 1H, CH

), 7.95 (dt, J=7.8, 1.2 Hz, 1H, CH

), 7.87 (dt, J=8.1, 2.1 Hz, 1H, CH_(at)), 7.80 (s, 1H, CH_(at)),7.34-7.29 (m, 1H, CH_(at)), 7.10 (dd, J=5.7, 1.2 Hz, 1H, CH

). MS: MH⁺=256.

EXAMPLE 29

Synthesis of 4-(6-bromopyridin-2yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

4-(6-bromopyridin-2-yl)-N-(pyrimidin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-aminewas synthesized from 2-bromo-1-(6-bromo-pyridin-2-yl)-ethanone andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a gray solid. ¹H NMR (300 MHz, DMSO-₆): δ 11.92 (s, 1H, NH),8.65 (d, J=4.5 Hz, 2H, CH

), 7.95 (dd, J=7.8, 0.9 Hz, 1H, CH

), 7.82 (t, J=8.1 Hz, 1H, CH

), 7.75 (d, J=0.6 Hz, 1H, CH

), 7.54 (dd, J=8.1, 0.9 Hz, 1H, CH

, 7.05 (t, J=4.8 Hz, 1H, CH

). MS: MH⁺=334.

EXAMPLE 30

Synthesis of 4-(4-methylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

4-(4-methylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-1-(4-methyl-pyridin-2-yl)-ethanone andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a dark gray solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.81 (s, 1H,NH), 8.64 (d, J=4.8 Hz, 2H, CH

), 8.42 (dd, J=4.2, 0.6 Hz, 1H, CH

), 7.82 (t, J=0.9 Hz, 1H, CH

), 7.70 (s, 1H, CH

), 7.14-7.12 (m, 1H, CH

), 7.04 (t, J=4.8 Hz, 1H, CH

), 2.36 (s, 3H, ArCH₃). MS: MH⁺=270.

EXAMPLE 31

Synthesis of4-(3,5dimethylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

4-(3,5-dimethylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-1-(3,5-dimethyl-pyridin-2-yl)-ethanone andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a light-gray solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.70 (s,1H, NH), 8.64 (d, J=48 Hz, 2H, CH

), 8.24 (s, 1H, CH

), 7.46 (s, 1H, CH

), 7.41 (s, 1H, CH

), 7.02 (t, J=4.8 Hz, 1H, CH

), 2.52 (s, 3y, ArCH₃), 2.27 (s,3H, ArCH₃). MS: MH⁺=284.

EXAMPLE 32

Synthesis of 6-(2-(pyrimidin-2-ylamino)thiazol-4-yl)pyridin-2-oldihydrochloride.

6-(2-(pyrimidin-2-ylamino)thiazol-4-yl)pyridin-2-ol dihydrochloride wassynthesized from 2-bromo-1-(6-hydroxy-pyridine-2-yl)-ethanonedihydrochloride and pyrimidin-2-yl-thiourea in the same manner asExample 20 to provide the produce as a gray solid. ¹H NMR (300 MHz,DMSO-d₆): δ 11.93 (s, 1H, NH), 8.64 (d, J=4.5 Hz, 2H, CH

), 7.92 (s, 1H, CH

), 7.53 (t, J=8.1 Hz, 1H, CH

), 7.05 (t, J=4.8 Hz, 1H, CH

), 6.89 (d, J=6.9 Hz, 1H, CH

), 6.33 (d, J=9.3 Hz, 1H, CH

). MS: MH⁺=272.

EXAMPLE 33

Synthesis of N-(pyrimidin-2-yl)-4-(quinolin-2-yl)thiazol-2-aminedihydrochloride.

N-(pyrimidin-2-yl)-4-(quinolin-2-yl)thiazol-2-amine dihydrochloride wassynthesized from 2-bromo-1-quinolin-2-yl-ethanone dihydrochloride andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a gray solid. ¹H NMR. (300 MHz, DMSO-d₆): δ 8.84 (d, J=9.0Hz, 1H, CH

), 8.70 (d, J=5.1 Hz, 1H, CH

), 8.56 (s, 1H, CH

), 8.38 (dd, J=87, 3.3 Hz, 1H, CH

), 8.16 (d, J=7.8 Hz, 1H, CH

), 7.96 (t, J=7.5 Hz, 1H, CH

), 7.75 (t, J=7.8 Hz, 1H, CH

), 7.10 (t, J=4.8 Hz, 1H, CH

). MS: MH⁺=306.

EXAMPLE 34

Synthesis of N-(5-chloropyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine.

N-(5-chloropyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-1-pyridin-2-yl-ethanone and(5-chloro-pyrimidin-2-yl)-thiourea in the same manner as Example 20 toprovide the product as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.11(s, 1H, NH), 8.74 (s, 2H, CH

), 8.58 (d, J=5.1 Hz, 1H, CH

), 7.97 (d, J=8.1 Hz, 1H, CH

), 7.87 (m, 1H, CH

), 7.76 (s, 1H, CH

), 7.31 (m, 1H, CH

). MS: MH⁺=290.

EXAMPLE 35

Synthesis of N-(5-bromopyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine.

N-(5-bromopyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-1-pyridin-2-yl-ethanone and(5-bromo-pyrimidin-2-yl)-thiourea in the same manner as Example 20 toprovide the product as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.10(s, 1H, NH), 8.79 (s, 2H, CH

), 8.58-8.57 (m, 1H, CH

), 7.96 (d, J=7.8 Hz, 1H, CH

), 7.86 (dt, J=8.1, 1.8 Hz, 1H, CH

), 7.77 (s, 1H, CH

), 7.33-7.28 (m, 1H, CH

). MS: MH⁺=334.

EXAMPLE 36

Synthesis of N-(4-methylpyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine.

N-(4-methylpyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-1-pyridin-2-yl-ethanone and(4-methyl-pyrimidin-2-yl)-thiourea in the same manner as Example 20 toprovide the product as a gray solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.74(s, 1H, NH), 8.57 (d, J=4.2 Hz, 1H, CH

), 8.48 (d, J=4.8 Hz, 1H, CH

), 7.96 (d, J=7.8 Hz, 1H, CH

), 7.86 (dt, J=7.5, 1.8 Hz, 1H, CH

), 7.71 (s, 1H, CH

), 7.31-7.27 (m, 1H, CH

), 6.92 (d, J=4.8 Hz, 1H, CH

), 2.44 (s, 3H, ArCH₃). MS: MH⁺=270.

EXAMPLE 37

Synthesis of4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)thiazol-2-amine.

4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)thiazol-2-aminewas synthesized from 2-bromo-1-pyridin-2-yl-ethanone and(4-trifluoromethyl-pyrimidin-2-yl)-thiourea in the same manner asExample 20 to provide the product as a gray solid. ¹H NMR (300 MHz,DMSO-d₆): δ 12.42 (s, 1H, NJ), 8.98 (d, J=4.5 Hz, 1H, CH

), 8.58 (d, J=5.7 Hz, 1H, CH

). MS: MH^(═)=324.

EXAMPLE 38

Synthesis of6-methyl-N-(4-(pyridin-2-yl)thiazol-2-yl)benzo[d]thiazol-2-amine.

6-methyl-N-(4-(pyridin-2-yl)thiazol-2-yl)benzo[d]thiazol-2-amine wassynthesized from 2-bromo-1-pyridin-2-yl-ethanone and(6-methyl-benzothiazol-2-yl)-thiourea in the same manner as Example 20to provide the product as a light-brown solid. ¹H NMR (300 MHz, CDCl₃):δ 8.62 (s, 1H, CH

), 8.13 (d, J=6.6 Hz, 1H, CH

), 7.82 (t, J=7.5 Hz, 1H, CH

), 7.64-7.59 (m, 1H, CH

), 7.52-7.48 (m, 2H, CH

), 7.23-7.18 (m, 2H, CH

), 2.44 (s, 3H, ArCH₃). MS: MH⁺=325.

EXAMPLE 39

Synthesis of5-methyl-5-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

5-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-1-pyridin-2-yl-propan-1-one andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a gray solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.63 (s, 1H, NH),8.61 (d, J=4.5 Hz, 3H, CH

), 7.97 (d, J=8.4 Hz, 1H, CH

), 7.84 (t, J=7.5 Hz, 1H, CH

), 7.28-7.24 (m, 1H, CH

), 7.01 (t, J=4.8 Hz, 1H, CH

), 2.72 (s, 3H, ArCH₃). MS: MH⁺=270.

EXAMPLE 40

Synthesis of 5-ethyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

5-Ethyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-1-pyridin-2-yl-butan-1-one andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a gray solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.61 (s, 1H, NH),8.62-8.59 (m, 3H, CH

), 7.97 (d, J=7.8 Hz, 1H, CH

), 7.84 (dt, J=7.8, 1.8 Hz, 1H, CH

), 7.28-7.24 (m,1H, CH

), 7.01 (t, J=4.8 Hz, 1H, CH

), 2.49-2.48 (m, 2H, ArCH₂, overlapped with the peaks of DMSO), 1.26 (t,J=7.5 Hz, 3H, CH₃). MS: MH⁺=284.

EXAMPLE 41

Synthesis of5-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-ylthiazol-2-amine.

5-isopropyl-4-(pyridin-5-yl)-N-(pyrimidin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-3-methyl-1-pyridin-2-yl-butan-1-one andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a light-gray solid. ¹H NMR (300 MHz, CDCl₃):δ 9.95 (s, 1H,NH), 8.67-8.66 (m, 3H, CH

), 7.88 (d, J=7.8 Hz, 1H, CH

), 7.73 (t, J=8.1 Hz, 1H, CH

), 7.17 (m, 1H, CH

), 6.89 (t, J=5.1 Hz, 1H, CH

), 4.35-4.30 (m, 1H, CH), 1.40 (d, J=6.6 Hz, 6H, C(CH₃)₂). MS: MH⁺=298.

EXAMPLE 42

Synthesis of5-pentyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

5-Pentyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine wassynthesized from 2-bromo-1-pyridin-2-yl-heptan-1-one andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a graph solid. ¹H NMR (300 MHz, CDCl₃) δ 10.07 (s, 1H, NH),8.66 (m, 3H, CH

), 7.88 (d, J=7.5 Hz, 1H, CH

), 7.73 (t, J=7.2 Hz, 1H, CH

), 7.16 (m, 1H, CH

), 6.89 (m, 1H, CH

), 3.29 (t, J=7.5 Hz, 2H, ArCH₂), 0.89 (m, 3H, CH₃). MS: MH⁺=326.

EXAMPLE 43

Synthesis of5-cyclohexyl-5-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-aminedihydrochloride.

5-Cyclohexyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-aminedihydrochloride was synthesized from2-bromo-2-cyclohexyl-1-pyridin-2-yl-ethanone dihydrochloride andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a light-yellow solid. ¹H NM$ (300 MHz, DMSO-d₆): δ 8.74 (d,J=4.5 Hz, 1H, CH

), 8.65 (d, J=4.8 Hz, 1H, CH

), 8.24 (t, J=8.1 Hz, 1H, CH

), 8.04 (d, J=8.7 Hz, 1H, CH

), 7.63 (t, J=6.3 Hz, 1H, CH

), 7.05 (t, J=4.8 Hz, 1H, CH

), 3.58 (m, 1H, CH), 2.02-1.29 (m, 10H, 5×CH₂). MS: MH⁺=338.

EXAMPLE 44

Synthesis of 5nonyl-5-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-1-amine.

5Nonyl-5-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-1-amine wassynthesized from 2-bromo-1-pyridin-2-yl-undecan-1-one andpyrimidin-2-yl-thiourea in the same manner as Example 20 to provide theproduct as a silver-gray solid. ¹H NMR (300 MHz, CDCl₃): δ 9.70 (s, 1H,NH), 8.64 (d, J=5.1 Hz, 3H, CH

), 7.88 (d, J=8.1 Hz, 1H, CH

), 7.72 (dt, J=7.8, 1.8 Hz, 1H, CH

), 7.19-7.14 (m, 1H, CH

), 6.89 (t, J=5.1 Hz, 1H, CH

), 3.29 (t, J=8.1 Hz, 2H, ArCH₂), 1.77-1.69 (m, 2H, CH₂), 1.40-125 (m,12H, 6×CH₂), 0.87 (t, J=6.9 Hz, 3H, CH₃). MS: MH⁺=382.

EXAMPLE 45

Synthesis ofN-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

To a stirred suspension of4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (51 mg, 0.2 mmol) indimethylformamide (4 mL), was added sodium hydride (60%, 12 mg, 0.3mmol), 2 minutes later, 2-iodopropane (20 μL, 0.2 mmol) was added. Thestirring was continued for 24 hours. The reaction was quenched with sat.ammonium chloride (10 mL) and extracted with ethyl acetate (15 mL×3 ).The combined organic layer was dried over anhydrous sodium sulfate,concentrated, and purified through silica gel column chromatography(ethyl acetate:hexanes=30:70) to afford 54 mg of compoundN-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine as whitesolid. ¹H NMR (300 MHz, CDCl₃): δ 8.59 (s, 3H, CH

), 8.15 (d, J=7.2 Hz, 1H, CH

, 7.77 (s, 2H, CH

), 7.19 (s, 1H, CH

), 6.85 (s, 1H, CH

, 5.85 (m, 1H, NCH), 1.69 (d, J=6.0 Hz, 6H, C(CH₃)₂). MS: MH⁺=298.

EXAMPLE 46

Synthesis ofN-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

N-methyl-3-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine wassynthesized from 4-pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine andiodomethane in the same manner as Example 45 to provide the produce as awhite solid in 50% yield. ¹H NMR (300 MHz, CDCl₃): δ 8.64-8.60 (m, 3H,CH

), 8.18-8.15 (m, 1H, CH

), 7.77 (dt, J=7.8, 1.8 Hz, 1H, CH

, 7.72 (s, 1H, CH

), 7.22-7.17 (m, 1H, CH

), 6.90 (t, J=.48 Hz, 1H, CH

), 4.07 (s, 3H, NCH₃). MS: MH⁺=270.

EXAMPLE 47

Synthesis of N-benzyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine

N-benzyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine wassynthesized from 4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine andbenzyl bromide in the same manner as Example 45 to provide the productas a white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.62-8.60 (m, 3H, CH

), 8.08 (d, J=7.8 Hz, 1H, CH

), 7.75-7.70 (m, 2H, CH

), 7.51 (d, J=7.2 Hz, 2H, CH

), 7.29-7.15 (m, 4H, CH

, overlapped with the peaks of CHCl₃), 6.88 (t, J=4.8 Hz, 1H, CH

), 5.98 (s, 2H, NCH₂Ar). MS: MH⁺=346.

EXAMPLE 48

Synthesis of2-((4-(pyridin-2-yl)thiazol-2-yl)(pyrimidin-2-yl)amino)ethanol.

2-((4-(pyridin-2-yl)thiazol-2-yl)(pyrimidin-2-yl)amino)ethanol wassynthesized from 4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine and2-bromoethanol in the same manner as Example 45 to provide the productas a white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.63-8.60 (m, 3H, CH

), 8.02 (d, J=7.8 Hz, 1H, CH

), 7.79-7.73 (m, 2H, CH

), 7.23-7.18 (m, 1H, CH

), 6.93 (t, J=4.8 Hz, 1H, CH

), 4.94 (t, J=5.1 Hz, 2H, NCH₂), 4.71 (t, J=4.5 Hz, 1H, OH), 4.20-4.15(m, 2H, OCH₂). MS: MH⁺=300.

EXAMPLE 49

Synthesis of 5-bromo-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine.

To a suspension of 4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine(102 mg, 0.4 mmol) in acetic acid (2mL), was added bromine at roomtemperature. Stirring was continued for 2 hours, and then ethyl acetate(20 mL) was added. The crude product was collected by filtration andre-crystallized in ethyl acetate to afford 130 mg of5-bromo-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine as yellowsolid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.73-8.67 (m, 3H, CH

), 8.10 (d, J=3.3 Hz, 2H, CH

), 7.57-7.53 (m, 1H, CH

), 78.11 (t, J=5.1 Hz 1H, CH

). MS: MH⁺=334.

EXAMPLE 50

Synthesis of(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methanol.

A suspension of 4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (51mg, 0.2 mmol) in tetrahydrofuran (4 mL) in a sealed tube, was treatedwith aq. formaldehyde (36.5%, 2mL), then triethylamine (0.6 mL). It washeated to 130° C. for 12 hours, then cooled down and concentrated. Theresidue was quenched with water (20 mL), stirred and filtered to givethe product, which was washed with water and ethyl acetate in sequenceand then dried under vacuum. 55 mg of pure compound(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methanol wasobtained as white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.63 (s, 1H, NH),8.63-8.59 (m, 3H, CH

), 8.00 (d, J=7.8 Hz, 1H, CH

), 7.87 (t, J=7.2 Hz, 1H, CH

), 7.30-7.26 (m, 1H, CH

, 7.02 (t, J=4.8 Hz, 1H, CH

), 5.81 (t, J=5.7 Hz, 1H, OH), 5.03 (d, J=5.7 Hz, 2H, OCH₂Ar). MS:MH⁺=286.

EXAMPLE 51

Synthesis of(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl acetate.

A suspension of(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methanol (29 mg.0.1 mmol) in 1,2-dichloroethane (DCE, 5mL), was treated with pyridine(81 μL, 1 mmol), followed by the addition of acetic anhydride (38 μL,0.4 mmol) at room temperature. Then it was heated to reflux for 5 hours.After cooling down, the reaction was quenched with water (50 mL), the pHwas adjusted to 10 by using powder sodium carbonate and extracted withdichloromethane (30 mL×4). The combined organic layer was dried oversodium sulfate, and then concentrated. The resulting residue wassuspended in ethyl acetate, filtered and further washed with ethylacetate. 28 mg of((4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl acetate aswhite solid. MS: MH+=281.

EXAMPLE 52

Synthesis of(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl butyrate.

(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl butyratewas synthesized from(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methanol andbutyric acid anhydride in the same manner as Example 49 to provide theproduct as a off-white solid in 57% yield. ¹H NMR (300 MHz, CDCl₃): δ9.84 (s, 1H, NJ), 8.68-864 (m, 3H, CH

, 7.98 (d, J=7.8 Hz, 1H, CH

), 7.75 (dt, J=7.8, 2.1 Hz, 1H, CH

), 7.20 (dt, J=6.3, 1.2 Hz, 1H, CH

), 6.93 (t, J=4.8 Hz, 1H, CH

), 5.85 (s, 2H, ArCH₂O), 2.38 (t, J=7.5 Hz, 2H, CH₂CO), 1.74-1.67 (m,2H, CH₂), 0.97 (t, J=7.5, 3H, CH₃). MS: MNa⁺=378.

EXAMPLE 53

Synthesis of ethyl4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate.

To a stirred solution of ethyl 3-oxo-3-(pyridin-2-yl)propanoate (1.16 g,6 mol) in CHCl₃ (20 mL) at 0° C., was added dropwise bromine (339 μL,6.6 mmol). The reaction mixture was firstly stirred at 40° C. for 1 hr,and then 70° C. for another hour. The solvent was evaporated to give thecrude ethyl 2-bromo-3-oxo-3-(pyridin-2-yl)propanoate hydrobromide.

A reaction mixture of crude ethyl2-bromo-3-oxo-3-(pyridin-2-yl)propanoate hydrobromide,1-(pyrimidin-2-yl)thiourea (617 mg, 4mmol), and triethylamine (1.94 mL,14 mmol) in ethanol (20 mL) was refluxed for 1 hour under argonatmosphere. After cooling to room temperature, the reaction mixture wasquenched with water (200 mL) and stirred for 30 minutes. Then it wasfiltered and the collected solid was slurried in ethyl acetate/hexanes(1:1, 20 mL). After filtration and drying under vacuum, 910 mg of ethyl4-(pyrimidin-2-ylamino)thiazole-5-carboxylate afforded as brown-reddishsolid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.34 (s, 1H, NH), 8.73 (d, J=4.5Hz, 2H, CH

), 8.60 (d, J=3.9 Hz, 1H, CH

), 7.86 (dt, J=7.8, 1.8 Hz, 1H, CH

, 7.65 (d, J=7.5 Hz, 1H, CH

), 7.43-7.38 (m, 1H, CH

, 7.14 (t, J=5.1 Hz, 1H, CH

), 4.12 (q, J=7.2 Hz, 2H, OCH₂), 1.12 (t, J=7.2 Hz, 3H, CH₃). MS:MH⁺=328.

EXAMPLE 54

Synthesis of ethyl4-(4-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate.

Ethyl4-(4-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylatewas synthesized from pyrimidin-2-yl-thiourea and3-(4-methyl-pyridin-2-yl)-3-oxo-propionic acid ethyl ester in the samemanner as Example 53 to provide the product as a gray solid. ¹H NMR (300MHz, CDCl₃): δ 8.72 (d, J=5.1 Hz, 2H, CH

), 8.59 (d, J=4.8 Hz, 1H, CH

), 7.62 (s, 1H, CH

), 7.15 (d, J=4.2 Hz, 1H, CH

), 6.98 (t, J=4.8 Hz, 1H, CH

), 4.28 (q, J=7.2 Hz, 2H, OCH₂), 2.43 (s, 3H, ArCH₃), 1.29 (t, J=7.2 Hz,3H, CH₃). MS: MH⁺=342.

EXAMPLE 55

Synthesis of ethyl4-(6-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate.

Ethyl4-(6-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylatewas synthesized from pyrimidin-2-yl-thiourea and3-(6-methyl-pyridin-2-yl)-3-oxo-propionic acid ethyl ester in the samemanner as Example 53 to provide the product as a brown-reddish solid. ¹HNMR (300 MHz, CDCl₃): δ 9.95 (s, 1H, NJ), 8.71 (d, J=4.2 Hz, 2H, CH

), 7.66 (t, J=75 Hz, 1H, CH

), 7.56 (d, J=7.8 Hz, 1H, CH

), 7.20 (d, J=7.5 Hz, 1H, CH

), 6.98 (m, 1H, CH

), 4.26 (q, J=7.2 Hz, 2H, OCH₂), 2.66 (s, 3H, ArCH₃), 1.28 (t, J=7.2 Hz,3H, CH₃). MS: MH⁺=342.

EXAMPLE 56

Synthesis of ethyl2-((4-methylpyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate

Ethyl2-((4-methylpyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylatewas synthesized from (4-methyl-pyrimidin-2-yl)-thiourea and3-oxo-3-pyridin-2-yl-propionic acid ethyl ester in the same manner asExample 53 to provide the product as a brown-reddish solid. ¹H NMR (300MHz, CDCl₃): δ 9.43 (s, 1H, NH), 8.74 (d, J=4.5 Hz, 1H, CH

), 8.51 (d, J=5.4 Hz, 1H, CH

), 7.82-7.73 (m, 2H, CH

), 7.32 (t, J=5.7 Hz, 1H, CH

), 6.84 (d, J=5.4 Hz, 1H, CH

), 4.27 (q, J=7.2 Hz, 2H, OCH₂), 2.56 (s, 3H, ArCH₃), 1.28 (t, J=7.5 Hz,3H, CH₃). HS: MH⁺=342.

EXAMPLE 57

Synthesis of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid

To a solution of ethyl4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate (435 mg,1.33 mmol) in tetrahydrofuran/CH₃OH/H₂O (5:5:1, 16.5 mL) was addedlithium hydroxide monohydrate (391 mg, 9.31 mmol). The reaction mixturewas refluxed for 6 hours. After cooling down, the solvent was evaporatedand water (20 mL) was added to dissolve the residue. The pH was adjustedto 6 with aq. 6 M HCl and the mixture was stood at 4° C. for 16 hours.The precipitate was filtered, washed with water and dried under vacuumto give 385 mg of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid aslight-brown solid. MS: MNa⁺=322.

EXAMPLE 58

Synthesis of methyl4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate

A suspension of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid (60mg. 0.2 mmol) in methanol (10 mL) was treated with conc. sulfuric acid(˜98%, 2 drops). The reaction mixture was refluxed for 4 days. Aftercooling down, the solvent was evaporated and water (20 mL) was added.The pH was adjusted to 8 by sat. sodium bicarbonate and the mixture wasextracted with dichloromethane (20 mL×4). The combined organic layer wasdried over anhydrous sodium sulfate and then evaporated to afford 26 mgof methyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylateas white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.37 (s, 1H, NH), 8.72 (d,J=4.2 Hz, 2H, CH

), 8.60 (d, J=3.3 Hz, 1H, CH

), 7.86 (t, J=7.5 Hz, 1H, CH

), 7.66 (d, J=7.5 Hz, 1H, CH

), 7.41 (t, J=5.7 Hz, 1H, CH

, 7.14 (t, J=4.8 Hz, 1H, CH

), 3.67 (s, 3H, OCH₃). MS: MH⁺=314.

EXAMPLE 59

Synthesis of tert-butyl2-(tert-butyl(pyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate.

A mixture of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid (30mg. 0.1 mmol) and 1,1-di-tert-butoxy-N,N-dimethylmethanamine (120 μL,0.5 mmol) in toluene (2 mL) was heated to reflux for 24 hours. Aftercooling down, it was quenched with water (20 mL) and extracted withdichloromethane (10 mL×3). The combined organic layer was dried oversodium sulfate, concentrated, and then purified by preparative TLC(ethyl acetate:hexanes=30:70) to afforded 12 mg of tert-butyl2-(tert-butyl(pyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylateas white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.61 (d, J=4.8 Hz, 3H, CH

), 7.87 (dt, J=7.8, 1.5 Hz, 1H, CH

), 7.67 (d, J=7.8 Hz, 1H, CH

), 7.43-7.38 (m, 1H, CH

), 7.09 (t, J=4.8 Hz, 1H, CH

), 1.55 (s, 9H, C(CH₃)₃), 1.31 (s, 9H, C(CH₃)₃). MS: MH⁺=412.

EXAMPLE 60

Synthesis of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide.

In a sealed tube, a suspension of ethyl4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate (16 mg,0.05 mg) in 7M NH₃ solution in methanol (5 mL) was heated to 80° C. for7 days. The solvent was evaporated and the residue was washed with ethylacetate to to give the pure amide. It was suspended in methanol, treatedwith 4 M HCl in dioxane (0.4 mL) and heated to reflux. The solvent wasremoved by evaporation and the crude product was washed with ethylacetate to give 17 mg of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide aslight-yellow solid. ¹H NMR (300 MHz, CD₃OD): δ 8.93-8.89 (m, 2H, CH

), 8.71-8.63 (m, 3H, CH

), 8.04 (t, J=6.6 Hz, 1H, CH

), 7.14 (t, J=5.1 Hz, 1H, CH

). MS: MH⁺=299.

EXAMPLE 61

Synthesis ofN-methyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide.

A reaction mixture of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid (60mg, 0.2 mmol), methylamine hydrochloride (27 mg, 0.4 mmol),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP, 221 mg, 0.5 mmol), triethylamine (83 μL, 0.6mmol) in dimethylformamide (2mL) in a sealed tube was heated to 75° C.for 24 hours. Then it was quenched with water (20 mL), filtered andwashed with water. The solid was suspended in methanol (2mL) and treatedwith 4 M HCl in dioxane (0.6 mL). It was heated to reflux, and thenevaporated to remove solvent. The resulting solid was washed with ethylacetate and dried under vacuum to give 64 mg of theN-methyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamidehydrochloride as light-yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.85(m, 1H, CH

), 8.72 (d, J=4.8 Hz, 2H, Ch

, 8.93-8.29 (m, 2H Ch

), 7.72 (m, 1H, CH

), 7.13 (m, 1H, CH

), 2.85 (s, 3H, NCH₃). MS: MH⁺=313.

EXAMPLE 62

Synthesis ofN-benzyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide.

A reaction mixture of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid (60mg, 0.2 mmol), benzylamine (43 mg, 0.4 mmol),benzotriazole-1-yl-oxy-tris-dimethylamino)-phosphoniumhexafluorophosphate (BOP, 195 mg, 0.44 mmol), triethylamine (83 μL, 0.6mmol), in dimethylformamide (10 mL) was stirred for 4 days. Then it wasquenched with water (50 mL), filtered and washed with water. The solidwas suspended in methanol/dichloromethane (4:6) and then filtered. Thefiltrate was concentrated to give 24 mg of the amide as off-white solidin 31% yield. 8 mg of the above amide was suspended in methanol (1mL)and treated with 4 M HCl in dioxane (0.3 mL). It was heated to reflux,and then evaporated to remove solvent. The resulting solid was washedwith ethyl acetate and dried under vacuum to give 9 mgN-benzyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamidehydrochloride as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.29(br, 1H, NH), 12.09 (br, 1H, NJ), 8.71 (d, J=4.5 Hz, 2H, CH

), 8.40 (s, 1H, CH

), 8.32 (d, J=8.4 Hz, 1H, CH

), 8.09 (t, J=7.5 Hz, 1H, CH

), 7.51 (m, 1H, CH

), 7.37-7.28 (m, 5H, CH

), 7.11 (m, 1H, CH

), 4.52 (d, J=4.5 Hz, 2H, ArCH₂N). MS: MH⁺=389.

EXAMPLE 63

Synthesis of the MTX derivative,24-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-1,21-dioxo-1-(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-yl)-5,8,11,14,17-penta oxa-2,20-diazapentacosan-25-oic acidtri-trifluoroacetate

In a sealed tube, a reaction mixture of-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid (66mg, 0.22 mmol), tert-butyl1-amino-22-(4-(((2,4-diaminopteridin-6-yl)methyl(methyl)amino)benzamido)-19-oxo-3,6,9,12,15-pentaoxa-18-azatricosan-23-oate(MTX(CO₂Bu″)-(PEG)₆-NJ₂, 170 mg, 0.22 mmol),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP, 146 mg, 033 mmol), triethylamine (55 μL, 0.4mmol) in dimethylformamide (2 mL) was heated to 6° C. for 48 hours.After cooling to room temperature, it was quenched with water (30 mL),filtered and washed with water. The solid was dried, and then suspendedin a mixture of dichloromethane and methanol (6:4, 30 mL). It wasfiltered and the filtrate was concentrated to give the pure tert-butylester, which was treated with dichloromethane (10 mL), followed byaddition of trifluoroacetic acid (2mL). The mixture was stirred at roomtemperature for 24 hours and evaporated to give 268 mg of24-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-1,21-dioxo-1-(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-7)-5,8,11,14,17--pentaoxa-2,20--diazapentacosan-25-oic acid tri-trifluoroacetate asbrown-reddish solid. ¹H NMR (300 MHz, CD₃OD): δ 8.78 (d, J=4.5 Hz, 1H,CH

), 8.62-8.57 (m, 4H, CH

), 8.37 (t, J=7.8 Hz, 1H, CH

), 7.79 (t, J=6.3 Hz, 1H, CH

), 7.71 (d, J=9.0 Hz, 2H, CH

), 7.06 (t, J=4.8 Hz, 1H, CH_(ata)), 6.78 (d, J=8.7 Hz, 2H, CH

), 4.85 (s, 2H, ArCH₂N), 4.55-4.50 (m, 1H, CH), .370-3.42 (m, 24H), 3.21(s, 3H, NCH₃), 2.38-2.07 (m, 4H). MS: MNa⁺=1020.

EXAMPLE 64

Synthesis of the Biotin derivative, N-(31-oxo-35-((3aS, 4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-3,6,9,12,15,18,21,24,27-nonaoxa-30-azapentatriacontryl)-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-carboxamide

In a sealed tube, a reaction mixture of4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid (30mg, 0.1 mmol),N-(29-amino-3,6,9,12,15,18,21,24,27-nonaoxanonacosyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide(Biotin-(PEG)₁₀-NH₂, 68 mg, 0.1 mmol),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniuimhexafluorophosphate (BOP, 66 mg, 0.15 mmol), triethylamine (28 μL, 0.2mmol) in dimethylformamide (2mL) was heated to 60° C. for 48 hours.After cooling to room temperature, it was quenched with water (20 mL)and extracted with dichloromethane (20 mL×4). The combined organic layerwas dried over sodium sulfate, concentrated, and then purified bypreparative TLC (2 M NH₃ in methanol:dichloromethane=5:95) to afford 49mg ofN-(3-oxo-35-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-3,6,9,12,15,18,21,24,27-nonaoxa-30-azapentatriacontyl)-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamideas white solid. ¹H NMR (300 MHz, CD₃OD): δ 8.70 (m, 1H, CH

), 8.61 (d, J=4.8 Hz, 2H, CH

), 8.43 (d, J=8.1 Hz, 1H, CH

, 7.96 (t, J=7.8 Hz, 1H, CH

), 7.88 (s, 1H, NJ), 7.44 (t, J=5.7 Hz, 1H, CH

), 7.00 (t, J=4.8 Hz, 1H, CH

), 4.48-4.44 (m, 1H, CH), 4.29-4.25 (m, 1H, CH), 3.74-3.49 (m, 40H),3.18-3,12 (m, 1H, CH), 2.88 (dd, J=12.9, 5.4 Hz, 1H, CH), 2.68 (d,J=12.9 Hz, 1H, CH), 2.20-2.14 (m, 2H), 1.71-1.53 (m, 4H), 1.44-1.37 (m,2H). MS: MNa⁺=986.

EXAMPLE 65

Synthesis of 2-Bromo-3-oxo-3-pyridin-2-yl-propionitrile Hydrobromide

Bromine (4ml, 0.8 mmol, 1 eq) was added dropwise to a solution of3-oxo-3-pyridin-2-yl-propionitrile (117 mg, 0.8 mmol, 1 eq ) in CHCl₃ (5ml) at 0-5° C. Then the reaction mixture was heated to 40° C. for 1 hourand 70° C. for another hour. The reaction mixture was evaporated toremove the solvents and the crude product was used directly for nextstep.

EXAMPLE 66

Synthesis of4-Pyridin-2-yl-2-(pyrimidin-2-ylamino)-thiazole-5-carbonitril:

2-Bromo-3-oxo-3-pyridin-2-yl-propionitrile hydrobromide (46 mg, 0.3mmol), 1-(pyrimidin-2-yl)thiourea (0.6 mmol) and triethylamine (0.83 ml,6 mmol, 15 eq) were mixed together in ethanol (5 ml) under argon andrefluxed for 1 hour. After cooling to room temperature, the reaction wasquenched with water (10 ml) and then extracted with a 3 to 1 mixture ofmethanol and methylene chloride (1:3) (5 ml×3). The combined organicphase was evaporated. The title compound was obtained by columnchromatography. MS: MH+=281.

FORMULATIONS

The present invention also relates to compositions or formulations whichcomprise the substituted aminothiazoles according to the presentinvention. In general, the compositions of the present inventioncomprise an effective amount of one or more substituted aminothiazolesand salts thereof according to the present invention which are effectivefor providing treatment or preventing diseases that involve unregulatedcell growth; and one or more excipients. The compositions of the presentinvention also comprise an effective amount of one or more substitutedaminothiazoles and salts thereof according to the present inventionwhich are effective for treating or preventing diseases that involveinfection with a hepatitis virus; and one or more excipients.

For the purposes of the present invention the term “excipient” and“carrier” are used interchangeably throughout the description of thepresent invention and said terms are defined herein as, “ingredientswhich are used in the practice of formulating a safe and effectivepharmaceutical composition.”

The formulator will understand that excipients are used primarily toserve in delivering a safe, stable, and functional pharmaceutical,serving not only as part of the overall vehicle for delivery but also asa means for achieving effective absorption by the recipient of theactive ingredient. An excipient may fill a role as simple and direct asbeing an inert filler, or an excipient as used herein may be part of apH stabilizing system or coating to insure delivery of the ingredientssafely to the stomach. The formulator can also take advantage of thefact the compounds of the present invention have improved cellularpotency, pharmacokinetic properties, as well as improved oralbioavailability.

The present teachings also provide pharmaceutical compositions thatinclude at least one compound described herein and one or morepharmaceutically acceptable carriers, excipients, or diluents. Examplesof such carriers are well known to those skilled in the art and can beprepared in accordance with acceptable pharmaceutical procedures, suchas, for example, those described in Remington's Pharmaceutical Sciences,17the edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton,Pa. (1985), the entire disclosure of which is incorporated by referenceherein for all purposes. As used herein, “pharmaceutically acceptable”refers to a substance that is acceptable for use in pharmaceuticalapplications from a toxicological perspective and does not adverselyinteract with the active ingredient. Accordingly, pharmaceuticallyacceptable carriers are those that are compatible with the otheringredients in the formulation and are biologically acceptable.Supplementary active ingredients can also be incorporated into thepharmaceutical compositions.

Compounds of the present teachings can be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich can also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents, or encapsulating materials. The compoundscan be formulated in conventional manner, for example, in a mannersimilar to that used for known anti-cancer agents. The compounds canalso be formulated in conventional manner, for example, in a mannersimilar to that used for known anti-viral agents. Oral formulationscontaining a compound disclosed herein can comprise any conventionallyused oral form, including tablets, capsules, buccal forms, troches,lozenges and oral liquids, suspensions or solutions. In powders, thecarrier can be a finely divided solid, which is an admixture with afinely divided compound. In tablets, a compound disclosed herein can bemixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shaped and size desired. Thepowders and tablets can contain up to 99% of the compound.

Capsules can contain mixtures of one or more compound(s) disclosedherein with inert filler(s) and/or diluent(s) such as pharmaceuticallyacceptable starches (e.g., corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses (e.g., crystalline andmicrocrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants, surfacemodifying agents (including surfactants), suspending or stabilizingagents, including, but not limited to, magnesium stearate, stearic acid,sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, microcrystalline cellulose, sodiumcarboxymethyl cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodiumcitrate, complex silicates, calcium carbonate, glycine, sucrose,sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,mannitol, sodium chloride, low melting waxes, and ion exchange resins.Surface modifying agents include nonionic and anionic surface modifyingagents. Representative examples of surface modifying agents include, butare not limited to, poloxamer 188, benzalkonium chloride, calciumstearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitanesters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate,magnesium aluminum silicate, and triethanolamine. Oral formulationsherein can utilize standard delay or time-release formulations to alterthe absorption of the compound(s). The oral formulation can also consistof administering a compound disclosed herein in water or fruit juice,containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups, elixirs, and for inhaled delivery. A compound of thepresent teachings can be dissolved or suspended in a pharmaceuticallyacceptable liquid carrier such as water, an organic solvent, or amixture of both, or a pharmaceutically acceptable oils or fats. Theliquid carrier can contain other suitable pharmaceutical additives suchas solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators. Examples ofliquid carriers for oral and parenteral administration include, but arenot limited to, water (particularly containing additives as describedherein, e.g., cellulose derivatives such as a sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols andpolyhydric alcohols, e.g., glycols) and their derivatives, and oils(e.g., fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can be an oily ester such as ethyl oleateand isopropyl myristate. Sterile liquid carriers are used in sterileliquid form compositions for parenteral administration. The liquidcarrier for pressurized compositions can be halogenated hydrocarbon orother pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions orsuspension, can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, forexample, as tablets, capsules, powders, solutions, suspensions,emulsions, granules, or suppositories. In such form, the pharmaceuticalcomposition can be sub-divided in unit dose(s) containing appropriatequantities of the compound. The unit dosage forms can be packagedcompositions, for example, packeted powders, vials ampoules, prefilledsyringes or sachets containing liquids. Alternatively, the unit dosageform can be a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. Such unit dosage formcan contain from about 1 mg/kg of compound to about 500 mg/kg ofcompound, and can be given in a single dose or in two or more doses.Such doses can be administered in any manner useful in directing thecompound(s) to the recipient's bloodstream, including orally, viaimplants, parenterally (including intravenous, intraperitoneal andsubcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particulardisease state or disorder, it is understood that an effective dosage canvary depending upon the particular compound utilized, the mode ofadministration, and severity of the condition being treated, as well asthe various physical factors related to the individual being treated. Intherapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amountsufficient to cure or at least partially ameliorate the symptoms of thedisease and its complications. The dosage to be used in the treatment ofa specific individual typically must be subjectively determined by theattending physician. The variables involved include the specificcondition and its state as well as the size, age and response pattern ofthe patient.

In some cases it may be desirable to administer a compound directly tothe airways of the patient, using devices such as, but not limited,metered dose inhalers, breath-operated inhalers, multidose dry-powderinhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosoldispensers, and aerosol nebulizers. For administration by intranasal orintrabronchial inhalation, the compounds of the present teachings can beformulated into a liquid composition, a solid composition, or an aerosolcomposition. The liquid composition can include, by way of illustration,one or more compounds of the present teachings dissolved, partiallydissolved, or suspended in one or more pharmaceutically acceptablesolvents and can be administered by, for example, a pump or asqueeze-actuated nebulized spray dispenser. The solvents can be, forexample isotonic saline or bacteriostatic water. The solid compositioncan be, by way of illustration, a powder preparation including one ormore compounds of the present teachings intermixed with lactose or otherinert powders that are acceptable for intrabronchial use, and can beadministered by, for example, an aerosol dispenser or a device thatbreaks or punctures a capsule encasing the solid composition anddelivers the solid composition for inhalation. The aerosol compositioncan include, by way of illustration, one or more compounds of thepresent teachings, propellants, surfactants, and co-solvents, and can beadministered by, for example, a metered device. The propellants can be achlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or otherpropellants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parentally orintraperitoneally. Solutions or suspensions of these compounds or apharmaceutically acceptable salts, hydrates, or esters thereof can beprepared in water suitable mixed with a surfactant such ashydroxyl-propylcelluose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations typicallycontain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injection can include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In some embodiments, the form can sterile and its viscositypermits it to flow through a syringe. The form preferably is stableunder the conditions of manufacture and storage and can be preservedagainst the contaminating action of microorganisms such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

Compounds described herein can be administered transdermally, i.e.,administered across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministration can be carried out using the compounds of the presentteachings including pharmaceutically acceptable salts, hydrates, oresters thereof, in lotions, creams, foams, patches, suspensions,solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of atransdermal patch containing a compound, such as a compound disclosedherein, and a carrier that can be inert to the compound, can benon-toxic to the skin, and can allow delivery of the compound forsystemic absorption into the blood stream via the skin. The carrier cantake any number of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments can be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the compound can also be suitable. Avariety of occlusive devices can be used to release the compound intothe blood stream, such as a semi-permeable membrane covering a reservoircontaining the compound with or without a carrier, or a matrixcontaining the compound. Other occlusive devices are known in theliterature.

Compounds described herein can be administered rectally or vaginally inthe form of a conventional suppository. Suppository formulations can bemade from traditional materials, including cocoa butter, with or withoutthe addition of waxes to alter the suppository's melting point, andglycerin. Water-soluble suppository bases, such as polethylene glycolsof various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds ofthe present teachings into host cells either in vitro or in vivo. Lipidformulations and nanocapsules can be prepared by methods known in theart.

To increase the effectiveness of compounds of the present teachings, itcan be desirable to combine a compound with other agents effective inthe treatment of the target disease. For example, other active compounds(i.e., other active ingredients or agents) effective in treating thetarget disease can be administered with compounds of the presentteachings. The other agents can be administered at the same time or atdifferent times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment orinhibition of a pathological condition or disorder in a mammal, forexample, a human subject. The present teachings accordingly providemethods of treating or inhibiting a pathological condition or disorderby providing to a mammal a compound of the present teachings includingits pharmaceutically acceptable salt) or a pharmaceutical compositionthat includes one or more compounds of the present teachings incombination or association with pharmaceutically acceptable carriers.Compounds of the present teachings can be administered alone or incombination with other therapeutically effective compounds or therapiesfor the treatment or inhibition of the pathological condition ordisorder.

Non-limiting examples of compositions according to the present inventioninclude from about 0.001 mg to about 1000 mg of one or more according tothe present invention and one or more excipients; from about 1000 mg ofone or more according to the present invention and one or more accordingto the present invention and one or more excipients; and from about 0.1mg to about 10 mg of one or more substituted aminothiazoles according tothe present invention; and one or more excipients.

PROCEDURES

The following procedures can be utilized in evaluation and selectingcompounds as effective for providing treatment or preventing diseasesthat involve unregulated cell growth. The following procedures can alsobe utilized in evaluating and selecting compounds as effective fortreating or preventing diseases that involve infection with a hepatitisvirus.

Cell Cultures And Conditions

Huh-7 cells and derived from hepatocellular carcinoma cells, and weredonated by Dr. Xuanyong Lu, (Drexel University College of Medicine,Doylestown, Pa.). THLE-2 were purchased from American Type CultureCollection (Manassas, Va.). PH5CH were donated by Dr. Masayuki Noguchi(University of Tsukuba, Ibaraki, Japan). THLE-2 and PH5CH have beenimmortalized through stable transfection of the SV5 large T antigen innormal hepatocytes, and are thus cell lines that are representative ofnormal hepatocytes rather than HCC cells. THLE2 have been confirmed tonot form tumors in athymic mice. All cell lines were cultured andmaintained in 5% CO₂ at 37° C. Huh-7 were maintained in the culturemedia DMEM/F12 (Dulbecco's Modified Eagle medium) with 10% Fetal bovineserum (FBS), 100 μg/mL penicillin, 100 units/mL streptomycin, and 50μg/mL normocin. THLE-2and PH5CH were maintained in the culture mediaBrochial Epithelial Growth Media (BEGM) with 10% FBS, 100 μg/mLpenicillin, 100 units/mL streptomycin, with the following additives fromthe prepackaged kit: Bovine pituitary extract (BPE), insulin,hydrocortisone, retinoic acid, transferrin, triiodothyronine,supplemented with 5 ng/ml human epidermal growth factor and 70 ng/mlphosphoethanolamine (Lonza Walkersville Inc., Walkersville, Md.).

Testing Of Substituted Aminothiazole Analogues.

Huh7 cells were plated on 96-well plates at 2.0×10⁴ cells per well topermit grow in the presence of compounds of the disclosure. Compounds ofthe disclosure were prediluted and transferred to cell plates byautomated liquid handling. Cells were incubated with compounds of thedisclosure of 72 hours, after which culture growth and viability wereassessed by addition of 50 μg/mL3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)incubation for 4 hours at 37° C. Solubilization buffer (0.01M HCl, 10%SDS) was added followed by incubation at 37° C. overnight. Absorbancewas measured at 570 nm (reference 630 nm). Compound of the disclosurewere tested in in Huh 7, THLE-2 and PH5CH, over eight-point dilutions inhalf-log steps, testing 50.0, 16.6, 5.0, 1.66, 0.5, 0.166, 0.05, and0.016 μM in 0.5% DMSO, with each concentration in duplicate wells. Themean value of the reduction of viability signal in the MTT assay overthe duplicate wells was used to determine the concentration that iscytoxic to 50% of the cells (CC₅₀), and compared to DMSO-only controlwells (n=8), using curve-fitting analysis with XLfit (IDBS, Surrey, UK).Each compound was tested from 2 to 7 times in separate assay trials.

Selectivity of toxicity in HCC-derived cells over normal liver-derivedcells is important for the purposes of developing a therapy thatspecifically targets the cancer with low toxicity for the whole tumor.The Selective Index (SI) is the ratio of the CC₅₀ in normal cells (THLE2or PH5CH) over the CC₅₀ in the liver cancer derived cells; thus, thehigher the number, the lower the potential toxicity at an efficaciousdose.

TABLE 2 Exemplary cell viability screening results for compounds of thedisclosure with Huh-7 cells, THLE2 cells and PH5CH cells. Huh7 THLE2PH5CH CC₅₀ CC₅₀ THLE2/ CC₅₀ PH5CH/ Entry Structure (uM) (uM) Huh7 SI(uM) Huh7 SI 1

1.387 39.982 28.833 50.000 36.058 2

11.300 2.905 0.257 3

6.433 9.156 1.423 4

6.302 8.660 1.374 5

14.227 48.471 3.407 6

6.526 17.783 2.725 7

10.287 21.083 2.050 8

0.563 14.018 24.905 33.973 60.358 9

2.532 29.911 11.816 10

7.816 9.747 1.247 11

5.000 0.539 0.108 12

3.053 4.471 1.464 13

35.016 50.000 1.428 14

31.762 40.966 1.290 15

5.317 49.120 9.238 49.728 9.353 16

25.705 50.000 1.945 50.000 1.945 17

48.942 50.000 1.022 50.000 1.022 18

50.000 49.755 0.995 46.860 0.937 19

0.362 38.709 106.972 44.017 121.642 20

11.329 31.137 2.748 46.868 4.137 21

15.436 24.733 1.602 44.128 2.859 22

5.925 42.852 7.232 41.985 7.086 23

4.917 3.959 0.805 3.970 0.807 24

11.277 50.000 4.434 50.000 4.434 25

25.877 50.000 1.932 50.000 1.932 26

12.779 2.273 0.178 50.000 3.913 27

2.737 2.234 0.816 47.616 17.397 28

46.188 50.000 1.083 50.000 1.083 29

0.016 50.00 3125 50.00 3125 30

50.000 50.000 1.000 50.000 1.000 31

0.016 50.000 3125 50.000 3125 32

50.000 8.022 0.160 50.000 1.000 33

50.000 3.537 0.071 50.000 1.000 34

26.621 37.792 1.420 50.000 1.878 35

4.717 37.206 7.888 39.233 8.317 36

50.000 50.000 1.000 50.000 1.000 37

17.742 50.000 2.818 31.485 1.775 38

1.246 29.395 23.591 38.599 30.978 39

12.990 10.292 0.792 2.889 0.222 40

34.843 50.000 1.435 50.000 1.435 41

50.000 26.614 0.532 50.000 1.000 42

39.251 50.000 1.274 50.000 1.274 43

11.003 50.000 4.544 50.000 4.544 44

20.478 50.000 2.442 50.000 2.442 45

8.000 50.000 6.250 46

3.500 Not tested 47

0.016 50.000 3125.00 50.000 3125.00 48

1. A compound having formula (I):

Including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein: R¹ is selected from the groupconsisting of hydrogen, C₁-C₉ linear alkyl, isopropyl, cyclohexyl,bromine, cyano,

R² is selected from the group consisting of hydrogen, methyl, isopropyl,tert-butyl, benzyl, and

Ar¹ is selected from the group consisting of phenyl,

Ar² is selected from the group consisting of phenyl,

wherein compounds of the structures

are excluded from the compounds of formula (I).
 2. (canceled) 3.(canceled)
 4. (canceled)
 5. (canceled)
 6. The compound according toclaim 1, which is: 4-(pyridin-2-yl)-n-(pyrimidin-4-yl)thiazol-2-amine;4-(6-bromopyridin-2-yl)-n-(pyrimidin-2-yl)thiazol-2-amine;4-(4-methylpyridin-2-yl)-n-(pyrimidin-2-yl)thiazol-2-amine;4-(3,5-dimethylpyridin-2-yl)-n-(pyrimidin-2-yl)thiazol-2-amine;6-(2-(pyrimidin-2-ylamino)thiazol-4-yl)pyridin-2-ol;N-(pyrimidin-2-yl)-4-(quinolin-2-yl)thiazol-2-amine;N-(5-chloropyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;N-(5-bromopyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;N-(4-methylpyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine:4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)thiazol-2-amine;6-methyl-N-(4-(pyridin-2-yl)thiazol-2-yl)benzo[d]thiazol-2-amine;5-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-ethyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-pentyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-cyclohexyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-nonyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-benzyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;2-((4-(pyridin-2-yl)thiazol-2-yl)(pyrimidin-2-yl)amino)ethanol;5-bromo-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methanol;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl acetate;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl butyrate;Ethyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl4-(4-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate ;ethyl4-(6-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate ;ethyl2-((4-methylpyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate; 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid;methyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;tert-butyl2-(tert-butyl(pyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate;4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;N-methyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamideN-benzyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;24-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-1,21-dioxo-1-(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)-5,8,11,14,17-pentaoxa-2,20-diazapentacosan-25-oicacid;N-(31-oxo-35-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-3,6, 9, 12, 15, 18, 21, 24,27-nonaoxa-30-azapentatriacontyl)-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;4-Pyridin-2-yl-2-(pyrimidin-2-ylamino)-thiazole-5-carbonitrile; andpharmaceutically acceptable forms thereof.
 7. A composition comprisingan effective amount of at least one compound according to claim
 1. 8. Acomposition according to claim 7, further comprising at least oneexcipient.
 9. A composition according to claim 8, wherein the at leastone compound is at least one member selected from the group consistingof: 4-(pyridin-2-yl)-N-(pyrimidin-4-yl)thiazol-2-amine;4-(6-bromopyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;4-(4-methylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;4-(3,5-dimethylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;6-(2-(pyrimidin-2-ylamino)thiazol-4-yl)pyridin-2-ol;N-(pyrimidin-2-yl)-4-(quinolin-2-yl)thiazol-2-amine;N-(5-chloropyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;N-(5-bromopyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;N-(4-methylpyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine:4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)thiazol-2-amine;6-methyl-N-(4-(pyridin-2-yl)thiazol-2-yl)benzo[d]thiazol-2-amine;5-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-ethyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-pentyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-cyclohexyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-nonyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-benzyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;2-((4-(pyridin-2-yl)thiazol-2-yl)(pyrimidin-2-yl)amino)ethanol;5-bromo-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methanol;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl acetate;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl butyrate;Ethyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl4-(4-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl4-(6-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl 2-((4-methylpyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate;4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid;Methyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;tert-butyl2-(tert-butyl(pyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate;4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;N-methyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;N-benzyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;24-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-1,21-dioxo-1-(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)-5,8,11,14,17-pentaoxa-2,20-diazapentacosan-25-oicacid; N-(31-oxo-35-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-3, 6, 9, 12, 15, 18, 21, 24,27-nonaoxa-30-azapentatriacontyl)-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;4-Pyridin-2-yl-2-(pyrimidin-2-ylamino)-thiazole-5-carbonitrile andpharmaceutically acceptable forms thereof.
 10. (canceled)
 11. A methodfor treating a disease associated with unregulated cell growth, saidmethod comprising administering to a subject an effective amount of atleast one compound of the formula (I),

including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, to treat the disease wherein: R¹ isselected from the group consisting of hydrogen, C₁-C₉ linear alkyl,isopropyl, cyclohexyl, bromine, cyano,

R² is selected from the group consisting of hydrogen, methyl, isopropyl,tert-butyl, benzyl, and

Ar¹ is selected from the group consisting of phenyl,

Ar ² is selected from the group consisting of phenyl,


12. (canceled)
 13. The method of claim 11, wherein the at least onecompound is administered in a composition further comprising at leastone excipient.
 14. The method of claim 13, wherein the at least onecompound is at least one member selected from the group consisting of4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N,4-diphenylthiazol-2-amine; N-phenyl-4-(pyridin-2-yl)thiazol-2-amine;4-phenyl-N-(pyrimidin-2-yl)thiazol-2-amine;N,4-di(pyridin-2-yl)thiazol-2-amine;4-(pyridin-3-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;4-(pyridin-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-(pyrazin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;4-(pyridin-2-yl)-N-(pyrimidin-4-yl)thiazol-2-amine;4-(6-bromopyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;4-(4-methylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;4-(3,5-dimethylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;6-(2-(pyrimidin-2-ylamino)thiazol-4-yl)pyridin-2-ol;N-(pyrimidin-2-yl)-4-(quinolin-2-yl)thiazol-2-amine;N-(5-chloropyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;N-(5-bromopyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;N-(4-methylpyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine:4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)thiazol-2-amine;6-methyl-N-(4-(pyridin-2-yl)thiazol-2-yl)benzo[d]thiazol-2-amine;5-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-ethyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-pentyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-cyclohexyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-nonyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-benzyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;2-((4-(pyridin-2-yl)thiazol-2-yl)(pyrimidin-2-yl)amino)ethanol;5-bromo-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methanol;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl acetate;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl butyrate;Ethyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl4-(4-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl4-(6-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl2-((4-methylpyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate;4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid;Methyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;tert-butyl2-(tert-butyl(pyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate;4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;N-methyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;N-benzyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;24-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-1,21-dioxo-1-(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)-5,8,11,14,17-pentaoxa-2,20-diazapentacosan-25-oic acid;N-(31-oxo-35-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-3, 6, 9, 12, 15, 18, 21, 24,27-nonaoxa-30-azapentatriacontyl)-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino) thiazole-5-carboxamide;4-Pyridin-2-yl-2-(pyrimidin-2-ylamino)-thiazole-5-carbonitrile;3-(4-Phenyl-thiazol-2-ylamino)-phenol;(3-Chloro-2-methyl-phenyl)-(4-pyridin-2-yl-thiazol-2-yl)-amine; andpharmaceutically acceptable forms thereof.
 15. The method of claim 11,wherein the disease associated with unregulated cell growth is a cancerselected from the group consisting of hepatocellular carcinoma, primaryliver cancer, hepatoblastoma, breast cancer, ovarian cancer, lungcancer, leukemia and cholangiocarcinoma.
 16. (canceled)
 17. (canceled)18. (canceled)
 19. (canceled)
 20. (canceled)
 21. (canceled) 22.(canceled)
 23. (canceled)
 24. The method of claim 11, wherein thedisease associated with unregulated cell growth is metastatic disease.25. A method for treating a disease associated with infection of theliver with a virus, said method comprising administering to a subject aneffective amount of at least one compound of the formula (I),

including hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, to treat the disease wherein: R¹ isselected from the group consisting of hydrogen, C₁-C₉ linear alkyl,isopropyl, cyclohexyl, bromine, cyano,

R² is selected from the group consisting of hydrogen, methyl, isopropyl,tert-butyl, benzyl, and

Ar¹ is selected from the group consisting of phenyl,

Ar²is selected from the group consisting of phenyl,


26. (canceled)
 27. The method of claim 25, wherein the at least onecompound is administered in a composition further comprising at leastone excipient.
 28. The method of claim 27, wherein the at least onecompound is at least one member selected from the group consisting of4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N,4-diphenylthiazol-2-amine; N-phenyl-4-(pyridin-2-yl)thiazol-2-amine;4-phenyl-N-(pyrimidin-2-yl)thiazol-2-amine;N,4-di(pyridin-2-yl)thiazol-2-amine;4-(pyridin-3-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;4-(pyridin-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-(pyrazin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;4-(pyridin-2-yl)-N-(pyrimidin-4-yl)thiazol-2-amine;4-(6-bromopyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;4-(4-methylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;4-(3,5-dimethylpyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;6-(2-(pyrimidin-2-ylamino)thiazol-4-yl)pyridin-2-ol;N-(pyrimidin-2-yl)-4-(quinolin-2-yl)thiazol-2-amine;N-(5-chloropyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;N-(5-bromopyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine;N-(4-methylpyrimidin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine:4-(pyridin-2-yl)-N-(4-(trifluoromethyl)pyrimidin-2-yl)thiazol-2-amine;6-methyl-N-(4-(pyridin-2-yl)thiazol-2-yl)benzo[d]thiazol-2-amine;5-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-ethyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-pentyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-cyclohexyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;5-nonyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-isopropyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-methyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;N-benzyl-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;2-((4-(pyridin-2-yl)thiazol-2-yl)(pyrimidin-2-yl)amino)ethanol;5-bromo-4-(pyridin-2-yl)-N-(pyrimidin-2-yl)thiazol-2-amine;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methanol;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl acetate;(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)methyl butyrate;Ethyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl4-(4-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl4-(6-methylpyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;Ethyl 2-((4-methylpyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate;4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylic acid;Methyl 4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate;tert-butyl2-(tert-butyl(pyrimidin-2-yl)amino)-4-(pyridin-2-yl)thiazole-5-carboxylate;4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;N-methyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;N-benzyl-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;24-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-1,21-dioxo-1-(4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazol-5-yl)-5,8,11,14,17-pentaoxa-2,20-diazapentacosan-25-oicacid; N-(31-oxo-35-((3as,4s,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-3, 6, 9, 12, 15, 18, 21, 24,27-nonaoxa-30-azapentatriacontyl)-4-(pyridin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxamide;4-pyridin-2-yl-2-(pyrimidin-2-ylamino)-thiazole-5-carbonitrile;3-(4-phenyl-thiazol-2-ylamino)-phenol;(3-chloro-2-methyl-phenyl)-(4-pyridin-2-yl-thiazol-2-yl)-amine; andpharmaceutically acceptable forms thereof.
 29. The method of claim 25,wherein the virus is a hepatitis virus.
 30. The method of claim 25,wherein the hepatitis virus is the hepatits A virus.
 31. The method ofclaim 25, wherein the hepatitis virus is the hepatits B virus.
 32. Themethod of claim 25, wherein the hepatitis virus is the hepatits C virus.33. The method of claim 25, wherein the hepatitis virus is the hepatitsD virus.
 34. The method of claim 25, wherein the hepatitis virus is thehepatits E virus.
 35. The method of claim 25, wherein the virus is anyvirus infecting the liver